Triazolopyrimidines and related analogs as HSP90-inhibitors

ABSTRACT

Triazolopyrimidines and related compounds are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

This application relates and claims priority to U.S. ProvisionalApplication Ser. No. 60/504,135, filed Sep. 18, 2003, entitled NOVELHETEROCYCLIC COMPOUNDS AS HSP90 INHIBITORS and U.S. ProvisionalApplication Ser. No. 60/591,467, filed Jul. 26, 2004, entitled2-AMINOPURINE ANALOGS HAVING HSP90—INHIBITING ACTIVITY. This applicationalso relates to three other United States Utility Applications, entitled2-AMINOPURINE ANALOGS AS HSP90 INHIBITOR, PYRROLOPYRIMIDINES AND RELATEDANALOGS AS HSP90 INHIBITORS, and PYRAZOLOPYRIMIDES AND RELATED ANALOGSAS HSP90 INHIBITORS, which will be filed on the same date by the sameentity. This application further relates to International ApplicationPCT/US02/35069, filed Oct. 30, 2002, entitled PURINE ANALOGS HAVINGHSP90—INHIBITING ACTIVITY. All the above cited U.S. utilityapplications, provisional applications and international application areexpressly incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The invention relates in general to triazolopyrimidines and theirrelated analogs and their broad-spectrum utility, e.g., in inhibitingheat shock protein 90 (HSP90) to thereby treat or prevent HSP90-mediateddiseases.

BACKGROUND

HSP90s are ubiquitous chaperone proteins that are involved in folding,activation and assembly of a wide range of proteins, including keyproteins involved in signal transduction, cell cycle control andtranscriptional regulation. Researchers have reported that HSP90chaperone proteins are associated with important signaling proteins,such as steroid hormone receptors and protein kinases, including, e.g.,Raf-1, EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner J. TIBS1999, 24, 136-141; Stepanova, L. et al. Genes Dev. 1996, 10, 1491-502;Dai, K. et al. J. Biol. Chem. 1996, 271, 22030-4). Studies furtherindicate that certain co-chaperones, e.g., HSP70, p60/Hop/Sti1, Hip,Bag1, HSP40/Hdj2/Hsj 1, immunophilins, p23, and p50, may assist HSP90 inits function (see, e.g., Caplan, A. Trends in Cell Biol. 1999, 9,262-68).

Ansamycin antibiotics, e.g., herbimycin A (HA), geldanamycin (GM), and17-allylaminogeldanamycin (17-AAG) are thought to exert theiranticancerous effects by tight binding of the N-terminus pocket ofHSP90, thereby destabilizing substrates that normally interact withHSP90 (Stebbins, C. et al. Cell 1997, 89, 239-250). This pocket ishighly conserved and has weak homology to the ATP-binding site of DNAgyrase (Stebbins, C. et al., supra; Grenert, J. P. et al. J. Biol. Chem.1997, 272, 23843-50). Further, ATP and ADP have both been shown to bindthis pocket with low affinity and to have weak ATPase activity(Proromou, C. et al. Cell 1997, 90, 65-75; Panaretou, B. et al. EMBO J.1998, 17, 4829-36). In vitro and in vivo studies have demonstrated thatoccupancy of this N-terminal pocket by ansamycins and other HSP90inhibitors alters HSP90 function and inhibits protein folding. At highconcentrations, ansamycins and other HSP90 inhibitors have been shown toprevent binding of protein substrates to HSP90 (Scheibel, T. H. et al.Proc. Natl. Acad. Sci. USA 1999, 96, 1297-302; Schulte, T. W. et al. J.Biol. Chem. 1995, 270, 24585-8; Whitesell, L., et al. Proc. Natl. Acad.Sci. USA 1994, 91, 8324-8328). Ansamycins have also been demonstrated toinhibit the ATP-dependent release of chaperone-associated proteinsubstrates (Schneider, C. L. et al. Proc. Natl. Acad. Sci., USA 1996,93, 14536-41; Sepp-Lorenzino et al. J. Biol. Chem. 1995, 270,16580-16587). In either event, the substrates are degraded by aubiquitin-dependent process in the proteasome (Schneider, C. L., supra;Sepp-Lorenzino, L., et al. J. Biol. Chem. 1995, 270, 16580-16587;Whitesell, L. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 8324-8328).

HSP90 substrate destabilization occurs in tumor and non-transformedcells alike and has been shown to be especially effective on a subset ofsignaling regulators, e.g., Raf (Schulte, T. W. et al. Biochem. Biophys.Res. Commun. 1997, 239, 655-9; Schulte, T. W., et al. J. Biol. Chem.1995, 270, 24585-8), nuclear steroid receptors (Segnitz, B.; U. GehringJ. Biol. Chem. 1997, 272, 18694-18701; Smith, D. F. et al. Mol. Cell.Biol. 1995, 15, 6804-12), v-Src (Whitesell, L., et al. Proc. Natl. Acad.Sci. USA 1994, 91, 8324-8328) and certain transmembrane tyrosine kinases(Sepp-Lorenzino, L. et al. J. Biol. Chem. 1995, 270, 16580-16587) suchas EGF receptor (EGFR) and HER2/Neu (Hartmann, F., et al. Int. J. Cancer1997, 70, 221-9; Miller, P. et al. Cancer Res. 1994, 54, 2724-2730;Mimnaugh, E. G., et al. J. Biol. Chem. 1996, 271, 22796-801; Schnur, R.et al. J Med Chem. 1995, 38, 3806-3812), CDK4, and mutant p53. Erlichmanet al. Proc. AACR 2001, 42, abstract 4474. The ansamycin-induced loss ofthese proteins leads to the selective disruption of certain regulatorypathways and results in growth arrest at specific phases of the cellcycle (Muise-Heimericks, R. C. et al. J. Biol. Chem. 1998, 273,29864-72), and apoptosis, and/or differentiation of cells so treated(Vasilevskaya, A. et al. Cancer Res., 1999, 59, 3935-40). Ansamycinsthus hold great promise for the treatment and/or prevention of manytypes of cancers and proliferative disorders, and also hold promise astraditional antibiotics. However, their relative insolubility makes themdifficult to formulate and administer, and they are not easilysynthesized and currently must, at least in part, be generated throughfermentation. Further, the dose limiting toxicity of ansamycins ishepatic.

In addition to anti-cancer and antitumorgenic activity, HSP90 inhibitorshave also been implicated in a wide variety of other utilities,including use as anti-inflammation agents, anti-infectious diseaseagents, agents for treating autoimmunity, agents for treating stroke,ischemia, multiple sclerosis, cardiac disorders, central nervous systemrelated disorders and agents useful in promoting nerve regeneration(See, e.g., Rosen et al. WO 02/09696 (PCT/US01/23640); Degranco et al.WO 99/51223 (PCT/US99/07242); Gold, U.S. Pat. No. 6,210,974 B1; DeFrancoet al., U.S. Pat. No. 6,174,875. Overlapping somewhat with the above,there are reports in the literature that fibrogenetic disordersincluding but not limited to scleroderma, polymyositis, systemic lupus,rheumatoid arthritis, liver cirrhosis, keloid formation, interstitialnephritis, and pulmonary fibrosis also may be treatable with HSP90inhibitors. Strehlow, WO 02/02123 (PCT/US01/20578). Still further HSP90modulation, modulators and uses thereof are reported in Application Nos.PCT/US03/04283, PCT/US02/35938, PCT/US02/16287, PCT/US02/06518,PCT/US98/09805, PCT/US00/09512, PCT/US01/09512, PCT/US01/23640,PCT/US01/46303, PCT/US0-1/46304, PCT/US02/06518, PCT/US02/29715,PCT/US02/35069, PCT/US02/35938, PCT/US02/39993, 60/293,246, 60/371,668,60/335,391, 60/128,593, 60/337,919, 60/340,762, 60/359,484 and60/331,893.

Recently, purine derivatives showing HSP90 inhibitory activity have beenreported, e.g., in PCT/US02/35069; PCT/US02/36075. Purine moieties arewell accepted bioisosteres for a variety of ATP-dependent moleculartargets, see, JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat. No.4,772,606; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO02/055082; WO 02/055083; European Patent 0178178; Eur. J. Med. Chem.1994, 29(1), 3-9; and J Het. Chem. 1990, 27(5), 1409. However, compoundshaving the desired potency, selectivity and pharmaceutical propertiesrequired for effective HSP90 inhibition in vivo have not been reported.Therefore, a need remains for additional novel and potent HSP90inhibitors that meet the demanding biological and pharmaceuticalcriteria required to proceed towards human clinical trials.

SUMMARY OF THE INVENTION

The present invention is directed towards heterocyclic compounds, inparticular towards triazolopyrimidines and related compounds that showbroad utility, e.g., in inhibiting HSP90 and treating and/or preventingdiseases that are HSP90-dependent.

In one aspect, the invention comprises the heterocyclic compounds asspecified below in Formulae A and I and compounds that are produced by asynthetic process of the invention. Also included in the scope of thepresent invention are stereoisomeric forms, including the individualenantiomers and diastereomers, racemic mixtures, and diastereomericmixtures, as well as polymorphs, solvates, esters, tautomers,pharmaceutically acceptable salts and prodrugs of these compounds.Stereoisomers of the compounds of the present invention may be isolatedby standard resolution techniques such as, for example, fractionalcrystallization and chiral column chromatography.

In one embodiment, the invention provides compounds of Formula A, or apolymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, which show utilityby inhibiting HSP90 and treating and/or preventing diseases that areHSP90-dependent.

wherein:

-   -   X¹ and X² are the same or different and each is nitrogen or        —CR⁶;    -   X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto        tautomer, —OR⁸, —CN, halogen, lower alkyl, or —C(O)R⁹;    -   X⁴ is nitrogen or —CR⁶ when X³ is nitrogen, and X⁴ is —CR⁶R⁷        when X³ is —CR³;    -   R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;    -   R² is —NR⁸R¹⁰;    -   R⁴ is —(CH₂)_(n)— wherein n=0-3, —C(O), —C(S), —SO₂—, or —SO₂N—;        and

R⁵ is alkyl, aromatic, heteroaromatic, alicyclic, or heterocyclic, eachof which is optionally bi-or tri-cyclic, and optionally substituted withH, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, loweralicyclic, aralkyl, aryloxyalkyl, alkoxyalkyl, perhaloalkyl,perhaloalkyloxy, perhaloacyl, —N₃, —SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂, or—NR⁸R¹⁰.

In certain embodiments, there are exclusionary provisos with respect tocompounds disclosed in JP 10025294; U.S. Pat. No. 4,748,177; U.S. Pat.No. 4,748,177; U.S. Pat. No. 6,369,092; WO 00/06573; WO 02/055521; WO02/055082; WO 02/055083; Eur. J. Med. Chem. 1994, 29(1), 3-9; and J.Het. Chem. 1990, 27(5), 1409, which disclose compounds with —R⁴R⁵comprising ribose or a derivative thereof, or a sugar or derivativethereof; and compounds where —R⁴R⁵ is a phosphonate or phosphonic acid,or is substituted with a phosphonate or phosphonic acid; or compoundswhere R⁴ is —CH₂— or —(CH₂)_(n)— that are connected through an oxygenatom to another group.

In another embodiment, the invention provides compounds of Formula I, ora polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, which show utilityfor inhibiting HSP90 and treating and/or preventing diseases that areHSP90-dependent,

wherein:

-   -   R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R⁴ is CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—;    -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents are selected from the group consisting of            halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,            —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl,            heteroaryl, alicyclic, lower heterocyclic, arylalkyl,            heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, or —C(O)R⁹;    -   R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,        lower heteroaryl, —NR¹⁰R¹⁰, or —OR¹¹, wherein R¹⁰ and R¹⁰ taken        together optionally form a ring of 3-7 ring atoms and optionally        1-3 of the ring atoms are heteroatoms selected from the group of        O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower heteroaryl, lower aryl,        lower alkenyl, or lower alkynyl,    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower        heteroaryl or lower aryl; and    -   R¹² is hydrogen or lower alkyl; provided that when R⁵ is        alicyclic, the ring system does not contain any        tetra-substituted sp³ ring carbons.

In another embodiment, the invention provides compounds, or a polymorph,solvate, ester, tautomer, diastereomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, which show utility for inhibitingHSP90 and treating and/or preventing diseases that are HSP90-dependent,that are prepared by the process comprising:

-   -   reacting a compound of formula Y and a compound of formula Z,        wherein:    -   Y is a represented by any one of the following formulae:    -   Z is L¹-R⁴—R⁵; wherein:        -   L^(l) is halogen, NR⁸R¹⁰ triflate, tosylate, or mesylate;        -   R⁴ is —CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—;        -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:            -   the aryl group is substituted with 3 to 5 substituents,            -   the heteroaryl group is substituted with 2 to 5                substituents,            -   the alicyclic group is substituted with 3 to 5                substituents,            -   the heterocyclic group is substituted with 3 to 5                substituents, and            -   the substituents are selected from the group consisting                of halogen, lower alkyl, lower alkenyl, lower alkynyl,                —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower                aryl, heteroaryl, alicyclic, lower heterocyclic,                arylalkyl, heteroarylalkyl, amino, alkylamino,                dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,                perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,                thiophene, furanyl, indole, indazole, phosphonates,                phosphates, phosphoramides, sulfonates, sulfones,                sulfates, sulphonamides, carbamates, ureas, thioureas                and thioamides, wherein R⁸ and R¹⁰ taken together                optionally form a ring of 3-7 ring atoms and optionally                1-3 of the ring atoms are heteroatoms selected from the                group of O, S and N;        -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,            lower aryl, lower heteroaryl, or —C(O)R⁹;        -   R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower            aryl, lower heteroaryl, —NR¹⁰R¹⁰, or —OR¹¹, wherein R¹⁰ and            R¹⁰ taken together optionally form a ring of 3-7 ring atoms            and optionally 1-3 of the ring atoms are heteroatoms            selected from the group of O, S and N;        -   R¹⁰ is hydrogen, lower alkyl, lower heteroaryl, lower aryl,            lower alkenyl, or lower alkynyl,        -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower            heteroaryl or lower aryl;        -   R¹² is hydrogen or lower alkyl;        -   R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;        -   R²² is —NR⁸R¹⁰;        -   R²⁴ is —NH₂, —NO₂ or —NO;        -   R²⁵ is halogen or —OH;        -   R²⁶ is —C(O)NH₂ or C(O)OEt; and        -   R²⁷ is —NH₂, —OH or halogen;    -   provided that when R⁵ is alicyclic, the ring system does not        contain any tetra-substituted Sp³ ring carbons.

In another aspect, the present invention is directed to pharmaceuticalcompositions comprising the compounds of the invention, in particular,the compounds of Formulae A or I, and compounds formed by the process ofthe invention, and their polymorphs, solvates, esters, tautomers,diastereomer, enantiomers, pharmaceutically acceptable salts andprodrugs thereof, and one or more pharmaceutical excipients, for use intreatment or prevention of diseases that are HSP90-dependent.

In another aspect, the invention features a method of treating anindividual having an HSP90-mediated disorder by administering to theindividual a pharmaceutical composition that comprises apharmaceutically effective amount of a compound of Formulae A or I, or apolymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the invention provides a method for treating anindividual having a disorder selected from the group of inflammatorydiseases, infections, autoimmune disorders, stroke, ischemia, cardiacdisorder, neurological disorders, fibrogenetic disorders, proliferativedisorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolicdiseases, and malignant disease.

In yet another embodiment, the invention provides a method for treatingan individual having a fibrogenetic disorder, such as, for example,scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, livercirrhosis, keloid formation, interstitial nephritis and pulmonaryfibrosis.

In another embodiment, the invention provides a combination therapycomprising the administration of a pharmaceutically effective amount ofa compound of Formulae A or I, or a polymorph, solvate, ester, tautomer,diastereomer, enantiomer, pharmaceutically acceptable salt and prodrugthereof, according to any of the preceding aspects or embodiments, andat least one therapeutic agent selected from the group of cytotoxicagents, anti-angiogenesis agents and anti-neoplastic agents. Theanti-neoplastic agent may be selected from the group of alkylatingagents, anti-metabolites, epidophyllotoxins antineoplastic enzymes,topoisomerase inhibitors, procarbazines, mitoxantrones, platinumcoordination complexes, biological response modifiers and growthinhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors.

Any of the above described aspects and embodiments of the invention canbe combined where practical.

The individual compounds, methods and compositions prescribed do notpreclude the utilization of other, unspecified steps and agents, andthose of ordinary skill in the art will appreciate that additional stepsand compounds may also be combined usefully within the spirit of variousaspects and embodiments of the invention.

Advantages of the invention depend on the specific aspect and embodimentand may include one or more of: ease of synthesis and/or formulation,solubility, and IC₅₀ relative to previously existing compounds in thesame or different classes of HSP90 inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

I. DEFINITIONS

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention, which, upon administrationto a recipient, is capable of providing, either directly or indirectly,a compound of this invention or a pharmaceutically active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowingorally administered compound to be more readily absorbed into blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system).

A “pharmaceutically acceptable salt” may be prepared for any compound ofthe invention having a functionality capable of forming a salt, forexample, an acid or base functionality. Pharmaceutically acceptablesalts may be derived from organic or inorganic acids and bases.Compounds of the invention that contain one or more basic functionalgroups, e.g., amino or alkylamino, are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptableorganic and inorganic acids. These salts can be prepared in situ duringthe final isolation and purification of the compounds of the invention,or by separately reacting a purified compound of the invention in itsfree base form with a suitable organic or inorganic acid, and isolatingthe salt thus formed. Examples of suitable acid salts include acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate,2-napthalenesulfonate, nicotinate, nitrate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, salicylate, succinate, sulfate, tartrate, thiocyanate,tosylate and undeconate. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts. See, e.g., Berge et al. “Pharmaceutical Salts”, J. Pharm. Sci.1977, 66:1-19.

Compounds of the present invention that contain one or more acidicfunctional groups are capable of forming pharmaceutically acceptablesalts with pharmaceutically acceptable bases. The term “pharmaceuticallyacceptable salts” in these instances refers to the relatively non-toxic,inorganic and organic base addition salts of compounds of the presentinvention. These salts can likewise be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form with a suitable base, suchas the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation, with ammonia, or with a pharmaceuticallyacceptable organic primary, secondary or tertiary amine. Representativealkali or alkaline earth salts include the lithium, sodium, potassium,calcium, magnesium, and aluminum salts and the like. Illustrativeexamples of some of the bases that can be used include sodium hydroxide,potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄alkyl)₄, and the like. Representative organic amines useful for theformation of base addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water oroil-soluble or dispersible products may be obtained by suchquaternization. See, for example, Berge et al., supra.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates,phosphate esters, metal salts and sulfonate esters.

Suitable positions for derivatization of the compounds of the inventionto create “prodrugs” include but are not limited, 2-amino substitution.Those of ordinary skill in the art have the knowledge and means toaccomplish this without undue experimentation. Various forms of prodrugsare well known in the art. For examples of such prodrug derivatives,see, e.g.,

-   -   a) Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and        Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985,        vol. 42, p. 309-396;    -   b) Bundgaard, H. “Design and Application of Prodrugs” in A        Textbook of Drug Design and Development, Krosgaard-Larsen and H.        Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and    -   c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.        Each of which is incorporated herein by reference.

The term “prodrugs” as employed herein includes, but is not limited to,the following groups and combinations of these groups:

Amine Prodrugs:

Hydroxy Prodrugs:

-   -   Acyloxyalkyl esters;    -   Alcoxycarbonyloxyalkyl esters;    -   Alkyl esters;    -   Aryl esters;    -   Disulfide containing esters.

The term “alkyl,” alone or in combination, refers to an optionallysubstituted straight-chain, or optionally substituted branched-chainsaturated hydrocarbon radical having from one to about thirty carbons,more preferably one to twelve carbons. Examples of alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and thelike. The term “cycloalkyl” embraces cyclic alkyl radicals which includemonocyclic, bicyclic, tricyclic, and higher multicyclic alkyl radicalswherein each cyclic moiety has from three to about eight carbon atoms.Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. A “lower alkyl” is a shorteralkyl, e.g., one containing from one to about six carbon atoms.

The term “alkenyl,” alone or in combination, refers to an optionallysubstituted straight-chain, or optionally substituted branched-chainhydrocarbon radical having one or more carbon-carbon double-bonds andhaving from two to about thirty carbon atoms, more preferably two toabout eighteen carbons. Examples of alkenyl radicals include ethenyl,propenyl, butenyl, 1,3-butadienyl and the like. The term “cycloalkenyl”refers to cyclic alkenyl radicals which include monocyclic, bicyclic,tricyclic, and higher multicyclic alkenyl radicals wherein each cyclicmoiety has from three to about eight carbon atoms. A “lower alkenyl”refers to an alkenyl having from two to about six carbons.

The term “alkynyl,” alone or in combination, refers to an optionallysubstituted straight-chain or optionally substituted branched-chainhydrocarbon radical having one or more carbon-carbon triple-bonds andhaving from two to about thirty carbon atoms, more preferably from twoto about twelve carbon atoms, from two to about six carbon atoms as wellas those having from two to about four carbon atoms. Examples of alkynylradicals include ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and thelike. The term “cycloalkynyl” refers to cyclic alkynyl radicals whichinclude monocyclic, bicyclic, tricyclic, and higher multicyclic alkynylradicals wherein each cyclic moiety has from three to about eight carbonatoms. A “lower alkynyl” refers to an alkynyl having from two to aboutsix carbons.

The terms “heteroalkyl, heteroalkenyl and heteroalkynyl” includeoptionally substituted alkyl, alkenyl and alkynyl structures, asdescribed above, and which have one or more skeletal chain atomsselected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur,phosphorous or combinations thereof.

The term “carbon chain” embraces any alkyl, alkenyl, alkynyl, orheteroalkyl, heteroalkenyl, or heteroalkynyl group, which are linear,cyclic, or any combination thereof. If the chain is part of a linker andthat linker comprises one or more rings as part of the core backbone,for purposes of calculating chain length, the “chain” only includesthose carbon atoms that compose the bottom or top of a given ring andnot both, and where the top and bottom of the ring(s) are not equivalentin length, the shorter distance shall be used in determining the chainlength. If the chain contains heteroatoms as part of the backbone, thoseatoms are not calculated as part of the carbon chain length.

The term “membered ring” can embrace any cyclic structure, includingaromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fusedring systems as described below. The term “membered” is meant to denotethe number of skeletal atoms that constitute the ring. Thus, forexample, pyridine, pyran, and pyrimidine are six-membered rings andpyrrole, tetrahydrofuran, and thiophene are five-membered rings.

The term “aryl,” alone or in combination, refers to an optionallysubstituted aromatic hydrocarbon radical of six to about twenty ringatoms, and includes mono-aromatic rings and fused aromatic ring. A fusedaromatic ring radical contains from two to four fused rings where thering of attachment is an aromatic ring, and the other individual ringswithin the fused ring may be aromatic, heteroaromatic, alicyclic orheterocyclic. Further, the term aryl includes mono-aromatic ring andfused aromatic rings containing from six to about twelve carbon atoms,as well as those containing from six to about ten carbon atoms. Examplesof aryl groups include, without limitation, phenyl, naphthyl, anthryl,chrysenyl, and benzopyrenyl ring systems. The term “lower aryl” refersto an aryl having six to about ten skeletal ring carbons, e.g., phenyland naphthyl ring systems.

The term “heteroaryl” refers to optionally substituted aromatic radicalscontaining from about five to about twenty skeletal ring atoms and whereone or more of the ring atoms is a heteroatom such as, for example,oxygen, nitrogen, sulfur, selenium and phosphorus. The term heteroarylincludes optionally substituted mono-heteroaryl radicals and fusedheteroaryl radicals having at least one heteroatom (e.g., quinoline,benzothiazole). A fused heteroaryl radical may contain from two to fourfused rings and where the ring of attachment is a heteroaromatic ring,the other individual rings within the fused ring system may be aromatic,heteroaromatic, alicyclic or heterocyclic. The term heteroaryl alsoincludes mono-heteroaryls or fused heteroaryls having from five to abouttwelve skeletal ring atoms, as well as those having from five to aboutten skeletal ring atoms. Examples of heteroaryls include, withoutlimitation, furanyl, benzofuranyl, chromenyl, pyridyl, pyrrolyl,indolyl, quinolinyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, benzothiozole, benzimidazole,benzoxazoles, benzothiadiazole, benzoxadiazole, benzotriazole,quinolines, isoquinolines, indoles, purinyl, indolizinyl, thienyl andthe like and their oxides. The term “lower heteroaryl” refers to aheteroaryl having five to about ten skeletal ring atoms, e.g., pyridyl,thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.

The term “alicyclic” alone or in combination, refers to an optionallysubstituted saturated or unsaturated nonaromatic hydrocarbon ring systemcontaining from three to about twenty ring atoms. The term alicyclicincludes mono-alicyclic and fused alicyclic radicals. A fused alicyclicmay contain from two to four fused rings where the ring of attachment isan alicyclic ring, and the other individual rings within thefused-alicyclic radical may be aromatic, heteroaromatic, alicyclic andheterocyclic. The term alicyclic also includes mono-alicyclic and fusedalicyclic radicals containing from three to about twelve carbon atoms,as well as those containing from three to about ten carbon atoms.Examples of alicyclics include, without limitation, cyclopropyl,cyclopropenyl, cyclobutyl, cyclopentyl, cyclodecyl, cyclododecyl,cyclopentadienyl, indanyl, and cyclooctatetraenyl ring systems. The term“lower alicyclic” refers to an alicyclic having three to about tenskeletal ring carbons, e.g., cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, decalinyl, and cyclohexyl.

The term “heterocyclic” refers to optionally substituted saturated orunsaturated nonaromatic ring radicals containing from five to abouttwenty ring atoms where one or more of the ring atoms are heteroatomssuch as, for example, oxygen, nitrogen, sulfur, and phosphorus. The termalicyclic includes mono-heterocyclic and fused heterocyclic ringradicals. A fused heterocyclic radical may contain from two to fourfused rings where the attaching ring is a heterocyclic, and the otherindividual rings within the fused heterocyclic radical may be aromatic,heteroaromatic, alicyclic or heterocyclic. The term heterocyclic alsoincludes mono-heterocyclic and fused alicyclic radicals having from fiveto about twelve skeletal ring atoms, as well as those having from fiveto about ten skeletal ring atoms. Example of heterocyclics includewithout limitation, tetrahydrofuranyl, benzodiazepinyl,tetrahydroindazolyl, dihyroquinolinyl, and the like. The term “lowerheterocyclic” refers to a heterocyclic ring system having five to aboutten skeletal ring atoms, e.g., dihydropyranyl, pyrrolidinyl, indolyl,piperidinyl, piperazinyl, and the like.

The term “alkylaryl,” alone or in combination, refers to an aryl radicalas defined above in which one H atom is replaced by an alkyl radical asdefined above, such as, for example, tolyl, xylyl and the like.

The term “arylalkyl,” or “araalkyl,” alone or in combination, refers toan alkyl radical as defined above in which one H atom is replaced by anaryl radical as defined above, such as, for example, benzyl,2-phenylethyl and the like.

The term “heteroarylalkyl” refers to an alkyl radical as defined abovein which one H atom is replaced by a heteroaryl radical as definedabove, each of which may be optionally substituted.

The term “alkoxy,” alone or in combination, refers to an alkyl etherradical, alkyl-O—, wherein the term alkyl is defined as above. Examplesof alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term “aryloxy,” alone or in combination, refers to an aryl etherradical wherein the term aryl is defined as above. Examples of aryloxyradicals include phenoxy, benzyloxy and the like.

The term “alkylthio,” alone or in combination, refers to an alkyl thioradical, alkyl-S—, wherein the term alkyl is as defined above.

The term “arylthio,” alone or in combination, refers to an aryl thioradical, aryl-S—, wherein the term aryl is as defined above.

The term “heteroarylthio” refers to the group heteroaryl-S—, wherein theterm heteroaryl is as defined above.

The term “acyl” refers to a radical —C(O)R where R includes alkyl,alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkylor heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroaryl alkylgroups may be optionally substituted.

The term “acyloxy” refers to the ester group —OC(O)R, where R is H,alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic,arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl,heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may beoptionally substituted.

The term “carboxy esters” refers to —C(O)OR where R is alkyl, aryl orarylalkyl, wherein the alkyl, aryl and arylalkyl groups may beoptionally substituted.

The term “carboxamido” refers to

-   -   where each of R and R′ are independently selected from the group        consisting of H, alkyl, aryl, heteroaryl, alicyclic,        heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl,        aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups        may be optionally substituted.

The term “oxo” refers to ═O.

The term “halogen” includes F, Cl, Br and I.

The terms “haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy” includealkyl, alkenyl, alkynyl and alkoxy structures, as described above, thatare substituted with one or more fluorines, chlorines, bromines oriodines, or with combinations thereof.

The terms “perhaloalkyl, perhaloalkyloxy and perhaloacyl” refer toalkyl, alkyloxy and acyl radicals as described above, that all the Hatoms are substituted with fluorines, chlorines, bromines or iodines, orcombinations thereof.

The terms “cycloalkyl, arylalkyl, aryl, heteroaryl, alicyclic,heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl, and heteroalkyl”include optionally substituted cycloalkyl, arylalkyl, aryl, heteroaryl,alicyclic, heterocyclic, alkyl, alkynyl, alkenyl, haloalkyl andheteroalkyl groups.

The terms “alkylamino”, refers to the group —NHR where R isindependently selected from alkyl.

The terms “dialkylamino”, refers to the group —NRR′ where R and R′ arealkyls.

The term “sulfide” refers to a sulfur atom covalently linked to twoatoms; the formal oxidation state of said sulfur is (II). The term“thioether” may be used interchangeably with the term “sulfide.”

The term “sulfoxide” refers to a sulfur atom covalently linked to threeatoms, at least one of which is an oxygen atom; the formal oxidationstate of said sulfur atom is (IV).

The term “sulfone” refers to a sulfur atom covalently linked to fouratoms, at least two of which are oxygen atoms; the formal oxidationstate of said sulfur atom is (VI).

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “aryl optionally mono-or di-substituted with an alkyl” means that the alkyl may but need notbe present, or either one alkyl or two may be present, and thedescription includes situations where the aryl is substituted with oneor two alkyls and situations where the aryl is not substituted with analkyl.

“Optionally substituted” groups may be substituted or unsubstituted. Thesubstituents of an “optionally substituted” group may include, withoutlimitation, one or more substituents independently selected from thefollowing groups or designated subsets thereof: lower alkyl, loweralkenyl, lower alkynyl, lower aryl, heteroaryl, alicyclic, heterocyclic,arylalkyl, heteroarylalkyl, lower alkoxy, lower aryloxy, amino,alkylamino, dialkylamino, diarylalkylamino, alkylthio, arylthio,heteroarylthio, oxo, oxa, carbonyl (—C(O)), carboxyesters (—C(O)OR),carboxamido (—C(O)NH₂), carboxy, acyloxy, —H, halo, —CN, —NO₂, —N₃, —SH,—OH, —C(O)CH₃, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine,pyridinyl, thiophene, furanyl, indole, indazole, esters, amides,phosphonates, phosphonic acid, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, thioalkyls. An optionally substituted group may beunsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃).

The term “pyridine-1-oxy” also means “pyridine-N-oxy.”

Some of the compounds of the present invention may contain one or morechiral centers and therefore may exist in enantiomeric anddiastereomeric forms. The scope of the present invention is intended tocover all isomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well. Further, it is possible using well known techniques toseparate the various forms, and some embodiments of the invention mayfeature purified or enriched species of a given enantiomer ordiastereomer.

A “pharmacological composition” refers to a mixture of one or more ofthe compounds described herein, or pharmaceutically acceptable saltsthereof, with other chemical components, such as pharmaceuticallyacceptable carriers and/or excipients. The purpose of a pharmacologicalcomposition is to facilitate administration of a compound to anorganism.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject agent fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being,compatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water;

-   -   (17) isotonic saline; (18) Ringer's solution; (19) ethyl        alcohol; (20) phosphate buffer solutions; and    -   (21) other non-toxic compatible substances employed in        pharmaceutical formulations. A physiologically acceptable        carrier should not cause significant irritation to an organism        and does not abrogate the biological activity and properties of        the administered compound.

An “excipient” refers to an inert substance added to a pharmacologicalcomposition to further facilitate administration of a compound. Examplesof excipients include but are not limited to calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils and polyethylene glycols.

A “pharmaceutically effective amount” means an amount which is capableof providing a therapeutic and/or prophylactic effect. The specific doseof compound administered according to this invention to obtaintherapeutic and/or prophylactic effect will, of course, be determined bythe particular circumstances surrounding the case, including, forexample, the specific compound administered, the route ofadministration, the condition being treated, and the individual beingtreated. A typical daily dose (administered in single or divided doses)will contain a dosage level of from about 0.01 mg/kg to about 50-100mg/kg of body weight of an active compound of the invention. Preferreddaily doses generally will be from about 0.05 mg/kg to about 20 mg/kgand ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such asclearance rate, half-life and maximum tolerated dose (MTD) have yet tobe determined but one of ordinary skill in the art can determine theseusing standard procedures.

In some method embodiments, the preferred therapeutic effect is theinhibition, to some extent, of the growth of cells characteristic of aproliferative disorder, e.g., breast cancer. A therapeutic effect willalso normally, but need not, relieve to some extent one or more of thesymptoms other than cell growth or size of cell mass. A therapeuticeffect may include, for example, one or more of 1) a reduction in thenumber of cells; 2) a reduction in cell size; 3) inhibition (i.e.,slowing to some extent, preferably stopping) of cell infiltration intoperipheral organs, e.g., in the instance of cancer metastasis; 3)inhibition (i.e., slowing to some extent, preferably stopping) of tumormetastasis; 4) inhibition, to some extent, of cell growth; and/or 5)relieving to some extent one or more of the symptoms associated with thedisorder.

As used herein, the term IC₅₀ refers to an amount, concentration ordosage of a particular test compound that achieves a 50% inhibition of amaximal response in an assay that measures such response. In some methodembodiments of the invention, the “IC₅₀” value of a compound of theinvention can be greater for normal cells than for cells exhibiting aproliferative disorder, e.g., breast cancer cells. The value depends onthe assay used.

By a “standard” is meant a positive or negative control. A negativecontrol in the context of HER2 expression levels is, e.g., a samplepossessing an amount of HER2 protein that correlates with a normal cell.A negative control may also include a sample that contains no HER2protein. By contrast, a positive control does contain HER2 protein,preferably of an amount that correlates with overexpression as found inproliferative disorders, e.g., breast cancers. The controls may be fromcell or tissue samples, or else contain purified ligand (or absentligand), immobilized or otherwise. In some embodiments, one or more ofthe controls may be in the form of a diagnostic “dipstick.”

By “selectively targeting” is meant affecting one type of cell to agreater extent than another, e.g., in the case of cells with high asopposed to relatively low or normal HER2 levels.

II. Compounds of the Invention

Compounds of the invention and their polymorphs, solvates, esters,tautomers, diastereomers, enantiomers, pharmaceutically acceptable saltsor prodrugs show utility for inhibiting HSP90 and treating andpreventing diseases that are HSP90-dependent.

One embodiment of the compounds of the invention is of Formula A:

or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   X¹ and X² are the same or different and each is nitrogen or        —CR⁶;    -   X³ is nitrogen or —CR³ wherein R³ is hydrogen, OH, a keto        tautomer, —OR⁸, —CN, halogen, lower alkyl, or —C(O)R⁹;    -   X⁴ is nitrogen or a group CR⁶ when X³ is nitrogen, and X₄ is        —CR⁶R⁷ when X₃ is —C³;    -   R¹ is halogen, —OR⁸, —SR⁸, or lower alkyl;    -   R² is —NR⁸R¹⁰;    -   R⁴ is —(CH₂)_(n)— wherein n=0-3, —C(O), —C(S), —SO₂—, or —SO₂N—;        and    -   R⁵ is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, each        of which is optionally bi-or tricyclic, and optionally        substituted with H, halogen, lower alkyl, lower alkenyl, lower        alkynyl, lower aryl, lower alicyclic, araalkyl, aryloxyalkyl,        alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N₃,        —SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂, or —NR⁸R¹⁰;    -   with the provisos that:    -   the one not found or described in one or more of JP 10025294;        U.S. Pat. No. 4,748,177; U.S. Pat. No. 4,748,177; U.S. Pat. No.        6,369,092; WO 00/06573; WO 02/055521; WO 02/055082; WO        02/055083; Eur. J. Med. Chem., 1994, 29(1), 3-9; and J. Het.        Chem. 1990, 27(5), 1409;    -   —R⁴R⁵ is not a ribose or derivative thereof, or a sugar or        derivative thereof;    -   —R⁴R⁵ is not a phosphonate or phosphonic acid, or substituted        with phosphonate or phosphonic acid; and    -   when R⁴ is (CH₂)_(n) where n=0 or 1, then R⁴ and R⁵ are not        connected with ‘O’, e.g., —CH₂—O—CH₂— or —CH₂—CH₂—O—CH₂—.

In one embodiment, the compound, tautomer, pharmaceutically acceptablesalt, or prodrug thereof of Formula A, X₁ and X₂ are the same ordifferent and each is nitrogen or —CR⁶; R¹ is halogen, —OR⁸, —SR⁸, orlower alkyl; R² is —NR⁸R¹⁰; R³ is hydrogen, —OH or keto tautomer, —OR⁸,halogen, —CN, lower alkyl, or —C(O)R⁹; R⁴ is —(CH₂)_(n)— wherein n=0-3,—C(O), —C(S), —SO₂—, or —SO₂N—; and R⁵ is alkyl, aromatic,heteroaromatic, alicyclic, heterocyclic, each of which is optionally bi-or tricyclic, and optionally substituted with H, halogen, lower alkyl,—SR⁸, —OR⁸, —CN, —CO₂R⁹, —NO₂ or —NR⁸R¹⁰; R⁸ is hydrogen, lower alkyl,lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lower heteroaryl,—NR⁸R¹⁰ or OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰ is hydrogenor lower alkyl.

In one embodiment, the compound, tautomer, pharmaceutically acceptablesalt thereof, or prodrug thereof of Formula A, R¹ is selected fromhalogen, hydroxyl, lower alkoxy, lower thioalkyl and C₁₋₄ alkyl; and R²is —NH₂.

In another embodiment, R⁴ is —(CH₂)_(n)—, wherein n=0-3.

In another embodiment, R¹ is selected from halogen, hydroxyl, loweralkoxy, lower thioalkyl or C₁₋₄ alkyl; optionally wherein R² is NH₂.

In another embodiment, R⁴ is —(CH₂)_(n)—, wherein n=0-3.

In another embodiment, R⁴ is —(CH₂)_(n)—, wherein n=0-3, R¹ is selectedfrom halogen, hydroxyl, lower alkoxy, lower thioalkyl, and C₁₋₄ alkyl,and R² is optionally NH₂.

In another embodiment, R¹ is halogen, hydroxyl, lower alkoxy, lowerthioalkyl, or C₁₋₄ alkyl; and R² is optionally NH₂, R⁴ is —(CH₂)—, andR⁵ is phenyl, benzyl, or pyridyl, all optionally substituted with H,halogen, lower alkyl, —SR⁸, —OR⁸ (or cyclic ethers such asmethylenedioxy), —CN, —CO₂R⁹, —NO₂, or —NR⁸R¹⁰; R⁸ is hydrogen, loweralkyl, lower aryl or —(CO)R⁹; R⁹ is lower alkyl, lower aryl, lowerheteroaryl, —NR⁸R¹⁰ or —OR¹¹; R¹¹ is lower alkyl or lower aryl; and R¹⁰is hydrogen or lower alkyl.

In another embodiment R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H orhalogen, and R⁵ is phenyl optionally substituted with H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, perhaloalkyl, perhaloalkyloxy, —CN,—NO₂, —NH₂ or —CO₂R¹¹.

In another embodiment, R¹ is halogen, R² is —NH₂, R⁴ is —CH₂—, R⁶ is H,and R⁵ is 2-halo-3,5-dimethoxyphenyl optionally substituted with H,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, perhaloalkyl,perhaloalkyloxy, —CN, —NO₂, —NH₂, or —CO₂R¹¹ at the para (4-) position.

In another embodiment, R¹ is chloro, R² is —NH₂, R⁴ is —CH₂—, R⁶ is Hand R⁵ is 2-chloro-3,4,5-trimethoxyphenyl.

In another embodiment, R¹ is chloro, R² is —NH₂, R⁴ is —CH₂—, R⁶ is Hand R⁵ is 2-bromo-3,4,5-trimethoxyphenyl. In other embodiments, R⁵ isselected from 2-iodo-3,4,5-trimethoxyphenyl,2-fluoro-3,4,5-trimethoxyphenyl, and 2-bromo-3,4,5-trimethoxyphenyl.

Any of the forgoing embodiments can be combined where feasible andappropriate.

In another aspect, the invention provides compounds of Formula IV:

or a polymorph, solvate, ester, tautomer, diastereomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   X₁ and X₂ are the same or different and each is nitrogen or CR⁶;    -   R₁ is halogen, —OR₈, —SR⁸, or lower alkyl;    -   R₂ is —NR⁸R₁₀;    -   R⁴ is —CH_(2n),— where n=0-3, —C(O), —C(S), —SO₂—, or —SO₂N—;    -   R₅ is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all        optionally bi-or tricyclic, and all optionally substituted with        H, halogen, lower alkyl, —SR₈, —OR₈, —CN, —CO₂R₉, —NO₂, or        —NR₈R₁₀;    -   R₈ is hydrogen, lower alkyl, lower aryl or —(CO)R₉;    -   R₉ is lower alkyl, lower aryl, lower heteroaryl, —NR₈R₁₀ or        —OR₁₁; R₁₁ is lower alkyl or lower aryl; and    -   R₁₀ is hydrogen or lower alkyl.

In one embodiment of the compounds of Formula IV, a tautomer,pharmaceutically acceptable salt thereof, or prodrug thereof, R¹ ishalogen, hydroxyl, lower alkoxy, lower thioalkyl, or C₁₋₄ alkyl; and R²is —NH₂.

In one embodiment of the compounds of Formula IV, a tautomer,pharmaceutically acceptable salt thereof, or prodrug thereof, R¹ ishalogen, hydroxyl, lower alkoxy, lower thioalkyl, or C₁₋₄ alkyl; and R²is —NH₂; R⁴ is —CH₂—, —C(O), —C(S), —SO₂—.

In one embodiment of the compounds of Formula IV, a tautomer,pharmaceutically acceptable salt thereof, or prodrug thereof, R¹ ishalogen or C₁₋₄ alkyl; and R² is NH₂, R⁴ is —CH₂—.

In one embodiment of the compounds of Formula IV, a tautomer,pharmaceutically acceptable salt thereof, or prodrug thereof, R¹ ishalogen, hydroxyl, lower alkoxy, lower thioalkyl, or C₁₋₄ alkyl; and R²is NH₂, R⁴ is —(CH₂)_(n)—, where n=0-3.

In one embodiment of the compounds of Formula IV, a tautomer,pharmaceutically acceptable salt, or prodrug thereof, R⁴ is —C(O) or—CH₂—; R¹ is halogen, lower alkoxy or C₁₋₄ alkyl; and R² is NH₂.

In another embodiment, the invention provides compounds of Formula I:

or a polymorph, solvate, ester, tautomer, enantiomer, diastereomer,pharmaceutically acceptable salt or prodrug thereof, wherein:

-   -   R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl;    -   R² is —NHR⁸;    -   R⁴ is —CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—;    -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:        -   the aryl group is substituted with 3 to 5 substituents,        -   the heteroaryl group is substituted with 2 to 5            substituents,        -   the alicyclic group is substituted with 3 to 5 substituents,        -   the heterocyclic group is substituted with 3 to 5            substituents, and        -   the substituents are selected from the group consisting of            halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,            —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl,            heteroaryl, alicyclic, lower heterocyclic, arylalkyl,            heteroarylalkyl, amino, alkylamino, dialkylamino,            diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy,            perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,            indole, indazole, phosphonates, phosphates, phosphoramides,            sulfonates, sulfones, sulfates, sulphonamides, carbamates,            ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ taken            together optionally form a ring of 3-7 ring atoms and            optionally 1-3 of the ring atoms are heteroatoms selected            from the group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, or —C(O)R⁹;    -   R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,        lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken        together optionally form a ring of 3-7 ring atoms and optionally        1-3 of the ring atoms are heteroatoms selected from the group of        O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower heteroaryl, lower aryl,        lower alkenyl, or lower alkynyl,    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower        heteroaryl or lower aryl; and    -   R¹² is hydrogen or lower alkyl; provided that when R⁵ is        alicyclic, the ring system does not contain any        tetra-substituted sp ring carbons.

In one embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, diastereomer, pharmaceuticallyacceptable salt or prodrug thereof, each of the aryl, heteroaryl,alicyclic or heterocyclic group is monocyclic or bicyclic.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, diastereomer, pharmaceuticallyacceptable salt or prodrug thereof, R¹ is halogen; and R² is —NHR⁸,where R⁸ is hydrogen or —C(O)R⁹.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NHR⁸, where R⁸ ishydrogen or —C(O)R⁹; and R⁴ is lower alkyl.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NHR⁸, where R⁸ ishydrogen or —C(O)R⁹; and R⁴ is —CHT¹²—.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NHR⁸, where R⁸ ishydrogen or —C(O)R⁹; and R⁴ is —CH₂—.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R² is —NHR⁸, where R⁸ is hydrogen or —C(O)R⁹; and R⁴is —CH₂—.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is halogen; R² is —NH₂, R⁴ is —CH₂—; and R⁵ isaryl or heteroaryl, wherein each of the aryl and heteroaryl ismonocyclic or bicyclic and is substituted with 3 to 5 substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo; R² is —NH₂, R⁴ is —CH₂—; andR⁵ is aryl or heteroaryl, wherein each of the aryl and heteroaryl ismonocyclic or bicyclic and is substituted with 3 to 5 substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is aphenyl having at least three substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂ and R⁵ is apyridyl having at least two substituents.

In another embodiment of the compounds of Formula I, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, R¹ is chloro or bromo, R² is —NH₂, and R⁵ is1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.

It should be understood that any of the foregoing embodiments can becombined where feasible and appropriate.

In another embodiment, the invention provides compounds, or polymorphs,solvates, esters, tautomers, pharmaceutically acceptable salts orprodrugs thereof, prepared by the process comprising:

-   -   reacting a compound of formula Y and a compound of formula Z,        wherein:    -   Y is a represented by any one of the following formulae:    -   Z is L¹-R⁴—R⁵; wherein:        -   L¹ is halogen, NR⁸R¹⁰, triflate, tosylate, or mesylate;        -   R⁴ is —CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—;        -   R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:            -   the aryl group is substituted with 3 to 5 substituents,            -   the heteroaryl group is substituted with 2 to 5                substituents,            -   the alicyclic group is substituted with 3 to 5                substituents,            -   the heterocyclic group is substituted with 3 to 5                substituents, and            -   the substituents are selected from the group consisting                of halogen, lower alkyl, lower alkenyl, lower alkynyl,                —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰, lower                aryl, heteroaryl, alicyclic, lower heterocyclic,                arylalkyl, heteroarylalkyl, amino, alkylamino,                dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,                perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,                thiophene, furanyl, indole, indazole, phosphonates,                phosphates, phosphoramides, sulfonates, sulfones,                sulfates, sulphonamides, carbamates, ureas, thioureas                and thioamides, wherein R⁸ and R¹⁰ taken together                optionally form a ring of 3-7 ring atoms and optionally                1-3 of the ring atoms are heteroatoms selected from the                group of O, S and N;    -   R⁸ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower        aryl, lower heteroaryl, or —C(O)R⁹;    -   R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,        lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken        together optionally form a ring of 3-7 ring atoms and optionally        1-3 of the ring atoms are heteroatoms selected from the group of        O, S and N;    -   R¹⁰ is hydrogen, lower alkyl, lower heteroaryl, lower aryl,        lower alkenyl, or lower alkynyl,    -   R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lower        heteroaryl or lower aryl;    -   R¹² is hydrogen or lower alkyl;    -   R²¹ is halogen, —OR⁸, —SR⁸ or lower alkyl;    -   R²² is —NR⁸R¹⁰;    -   R²⁴ is —NH₂, —NO₂ or —NO;    -   R²⁵ is halogen or —OH;    -   R²⁶ is —C(O)NH₂ or C(O)OEt; and    -   R²⁷ is —NH₂, —OH or halogen;        provided that when R⁵ is alicyclic, the ring system does not        contain any tetra-substituted sp³ ring carbons.

In one embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, L¹ is —Cl, —Br or —NH₂; R⁵ is arylor heteroaryl.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, R⁴ is —CH₂—.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, R⁵ is aryl, heteroaryl, alicyclic,or heterocyclic, optionally mono- or bicyclic.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, L¹ is —Cl, —Br or —NH₂; R⁴ is —CH₂—;and R⁵ is aryl or heteroaryl.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, Y is a triazolopyrimidine.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, Y is a triazole.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, Y is a pyrimidine.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, the reaction is performed in asolvent comprising a member selected from the group of DMF, THF andDMSO.

In another embodiment of the compounds prepared by the process of theinvention, or a polymorph, solvate, ester, tautomer, pharmaceuticallyacceptable salt or prodrug thereof, the reaction is performed in asolvent that comprises DMF.

It should be understood that any of the foregoing embodiments can becombined where feasible and appropriate.

Illustrative species of the compounds of the invention that are based onFormula I are described in TABLE 1. Prodrugs which can be employed bythese compounds include, but are not limited to, those listed in theDefinition section. TABLE 1 Exemplary Compounds of Formula I I

No. Ex. R¹ R⁴ R⁵ 1 5 Cl CH₂ 3,4,5-Trimethoxyphenyl 2 6 Cl CH₂2-Chloro-3,4,5-trimethoxyphenyl 3 8 Cl CH₂2-Bromo-3,4,5-trimethoxyphenyl 4 10 Cl CH₂ 2-Iodo-3,4,5-trimethoxyphenyl5 Cl CH₂ 2-Fluoro-3,4,5-trimethoxyphenyl 6 Cl CH₂ 3,4,5-Trimethyiphenyl7 Cl CH₂ 2-Chloro-3,4,5-trimethylphenyl 8 Cl CH₂2-Bromo-3,4,5-trimethylphenyl 9 Cl CH₂ 2-Iodo-3,4,5-trimethylphenyl 10Cl CH₂ 2-Fluoro-3,4,5-trimethylphenyl 11 Cl CH₂3,5-Dimethoxy-4-methylphenyl 12 Cl CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 13 Cl CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 14 Cl CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 15 Cl CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 16 Cl CH₂3,5-Dichloro-4-methylphenyl 17 Cl CH₂ 2,3,5-Trichloro-4-methylphenyl 18Cl CH₂ 2-Bromo-3,5-dichloro-4-methylphenyl 19 Cl CH₂2-Iodo-3,5-dichloro-4-methylphenyl 20 Cl CH₂2-Fluoro-3,5-dichloro-4-methylphenyl 21 Cl CH₂3,5-Dibromo-4-methylphenyl 22 Cl CH₂ 2-Chloro-3,5-dibromo-4-methylphenyl23 Cl CH₂ 2,3,5-Tribromo-4-methylphenylphenyl 24 Cl CH₂2-Iodo-3,5-dibromo-4-methylphenyl 25 Cl CH₂2-Fluoro-3,5-dibromo-4-methylphenyl 26 Cl CH₂3,5-Dichloro-4-methoxyphenyl 27 Cl CH₂ 2,3,5-Trichloro-4-methoxyphenyl28 Cl CH₂ 2-Bromo-3,5-dichloro-4-methoxyphenyl 29 Cl CH₂2-Iodo-3,5-dichloro-4-methoxyphenyl 30 Cl CH₂2-Fluoro-3,5-dichloro-4-methoxyphenyl 31 Cl CH₂3,5-Dibromo-4-methoxyphenyl 32 Cl CH₂2-Chloro-3,5-dibromo-4-methoxyphenyl 33 Cl CH₂2,3,5-Tribromo-4-methoxyphenyl 34 Cl CH₂2-Iodo-3,5-dibromo-4-methoxyphenyl 35 Cl CH₂2-Fluoro-3,5-dibromo-4-methoxyphenyl 36 Cl CH₂3-Chloro-5-bromo-4-methylphenyl 37 Cl CH₂2,3-Dichloro-5-bromo-4-methylphenyl 38 Cl CH₂2,5-Dibromo-3-chloro-4-methylphenyl 39 Cl CH₂2-Iodo-3-chloro-5-bromo-4-methylphenyl 40 Cl CH₂2-Fluoro-3-chloro-5-bromo-4-methylphenyl 41 Cl CH₂3-Chloro-5-bromo-4-methoxyphenylphenyl 42 Cl CH₂2,3-Dichloro-5-bromo-4-methoxyphenyl 43 Cl CH₂2,5-Dibromo-3-chloro-4-methoxyphenyl 44 Cl CH₂2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 45 Cl CH₂2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 46 Cl CH₂3-Bromo-5-chloro-4-methylphenyl 47 Cl CH₂2,5-Dichloro-3-bromo-4-methylphenyl 48 Cl CH₂2,3-Dibromo-5-chloro-4-methylphenyl 49 Cl CH₂2-Iodo-3-bromo-5-chloro-4-methylphenyl 50 Cl CH₂2-Fluoro-3-bromo-5-chloro-4-methylphenyl 51 Cl CH₂3-Bromo-5-chloro-4-methoxyphenyl 52 Cl CH₂2,5-Dichloro-3-bromo-4-methoxyphenyl 53 Cl CH₂2,3-Dibromo-5-chloro-4-methoxyphenyl 54 Cl CH₂2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 55 Cl CH₂2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 56 Cl CH₂3,5-Dimethoxy-4-trifluoromethylphenyl 57 Cl CH₂2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 58 Cl CH₂2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 59 Cl CH₂2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 60 Cl CH₂2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 61 Cl CH₂3,5-dibromo-4-trifluoromethoxyphenyl 62 Cl CH₂2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 63 Cl CH₂2,3,5-Tribromo-4-trifluoromethoxyphenyl 64 Cl CH₂2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 65 Cl CH₂2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 66 Cl CH₂3,5-Dimethyl-4-methoxyphenyl 67 Cl CH₂2-Chloro-3,5-dimethyl-4-methoxyphenyl 68 Cl CH₂2-Bromo-3,5-dimethyl-4-methoxyphenyl 69 Cl CH₂2-Iodo-3,5-dimethyl-4-methoxyphenyl 70 Cl CH₂2-Fluoro-3,5-dimethyl-4-methoxyphenyl 71 Cl CH₂3,5-Dimethyl-4-bromophenyl 72 Cl CH₂ 2-Chloro-3,5-dimethyl-4-bromophenyl73 Cl CH₂ 2,4-Dibromo-3,5-dimethylphenyl 74 Cl CH₂2-Iodo-3,5-dimethyl-4-bromophenyl 75 Cl CH₂2-Fluoro-3,5-dimethyl-4-bromophenyl 76 Cl CH₂3,5-Dimethyl-4-chlorophenyl 77 Cl CH₂ 2,4-Dichloro-3,5-dimethylphenyl 78Cl CH₂ 2-Bromo-3,5-dimethyl-4-chlorophenyl 79 Cl CH₂2-Iodo-3,5-dimethyl-4-chlorophenyl 80 Cl CH₂2-Fluoro-3,5-dimethyl-4-chlorophenyl 81 Br CH₂ 3,4,5-Trimethoxyphenyl 82Br CH₂ 2-Chloro-3,4,5-trimethoxyphenyl 83 Br CH₂2-Bromo-3,4,5-trimethoxyphenyl 84 Br CH₂ 2-Iodo-3,4,5-trimethoxyphenyl85 Br CH₂ 2-Fluoro-3,4,5-trimethoxyphenyl 86 Br CH₂3,4,5-Trimethylphenyl 87 Br CH₂ 2-Chloro-3,4,5-trimethylphenyl 88 Br CH₂2-Bromo-3,4,5-trimethylphenyl 89 Br CH₂ 2-Iodo-3,4,5-trimethylphenyl 90Br CH₂ 2-Fluoro-3,4,5-trimethylphenyl 91 Br CH₂3,5-Dimethoxy-4-methylphenyl 92 Br CH₂2-Chloro-3,5-dimethoxy-4-methylphenyl 93 Br CH₂2-Bromo-3,5-dimethoxy-4-methylphenyl 94 Br CH₂2-Iodo-3,5-dimethoxy-4-methylphenyl 95 Br CH₂2-Fluoro-3,5-dimethoxy-4-methylphenyl 96 Br CH₂3,5-Dichloro-4-methylphenyl 97 Br CH₂ 2,3,5-Trichloro-4-methylphenyl 98Br CH₂ 2-Bromo-3,5-dichloro-4-methylphenyl 99 Br CH₂2-Iodo-3,5-dichloro-4-methylphenyl 100 Br CH₂2-Fluoro-3,5-dichloro-4-methylphenyl 101 Br CH₂3,5-Dibromo-4-methylphenyl 102 Br CH₂2-Chloro-3,5-dibromo-4-methylphenyl 103 Br CH₂2,3,5-Tribromo-4-methylphenylphenyl 104 Br CH₂2-Iodo-3,5-dibromo-4-methylphenyl 105 Br CH₂2-Fluoro-3,5-dibromo-4-methylphenyl 106 Br CH₂3,5-Dichloro-4-methoxyphenyl 107 Br CH₂ 2,3,5-Trichloro-4-methoxyphenyl108 Br CH₂ 2-Bromo-3,5-dichloro-4-methoxyphenyl 109 Br CH₂2-Iodo-3,5-dichloro-4-methoxyphenyl 110 Br CH₂2-Fluoro-3,5-dichloro-4-methoxyphenyl 111 Br CH₂3,5-Dibromo-4-methoxyphenyl 112 Br CH₂2-Chloro-3,5-dibromo-4-methoxyphenyl 113 Br CH₂2,3,5-Tribromo-4-methoxyphenyl 114 Br CH₂2-Iodo-3,5-dibromo-4-methoxyphenyl 115 Br CH₂2-Fluoro-3,5-dibromo-4-methoxyphenyl 116 Br CH₂3-Chloro-5-bromo-4-methylphenyl 117 Br CH₂2,3-Dichloro-5-bromo-4-methylphenyl 118 Br CH₂2,5-Dibromo-3-chloro-4-methylphenyl 119 Br CH₂2-Iodo-3-chloro-5-bromo-4-methylphenyl 120 Br CH₂2-Fluoro-3-chloro-5-bromo-4-methylphenyl 121 Br CH₂3-Chloro-5-bromo-4-methoxyphenylphenyl 122 Br CH₂2,3-Dichloro-5-bromo-4-methoxyphenyl 123 Br CH₂2,5-Dibromo-3-chloro-4-methoxyphenyl 124 Br CH₂2-Iodo-3-chloro-5-bromo-4-methoxyphenyl 125 Br CH₂2-Fluoro-3-chloro-5-bromo-4-methoxyphenyl 126 Br CH₂3-Bromo-5-chloro-4-methylphenyl 127 Br CH₂2,5-Dichloro-3-bromo-4-methylphenyl 128 Br CH₂2,3-Dibromo-5-chloro-4-methylphenyl 129 Br CH₂2-Iodo-3-bromo-5-chloro-4-methylphenyl 130 Br CH₂2-Fluoro-3-bromo-5-chloro-4-methylphenyl 131 Br CH₂3-Bromo-5-chloro-4-methoxyphenyl 132 Br CH₂2,5-Dichloro-3-bromo-4-methoxyphenyl 133 Br CH₂2,3-Dibromo-5-chloro-4-methoxyphenyl 134 Br CH₂2-Iodo-3-bromo-5-chloro-4-methoxyphenyl 135 Br CH₂2-Fluoro-3-bromo-5-chloro-4-methoxyphenyl 136 Br CH₂3,5-Dimethoxy-4-trifluoromethylphenyl 137 Br CH₂2-Chloro-3,5-dimethoxy-4-trifluoromethylphenyl 138 Br CH₂2-Bromo-3,5-dimethoxy-4-trifluoromethylphenyl 139 Br CH₂2-Iodo-3,5-dimethoxy-4-trifluoromethylphenyl 140 Br CH₂2-Fluoro-3,5-dimethoxy-4-trifluoromethylphenyl 141 Br CH₂3,5-Dibromo-4-trifluoromethoxyphenyl 142 Br CH₂2-Chloro-3,5-dibromo-4-trifluoromethoxyphenyl 143 Br CH₂2,3,5-Tribromo-4-trifluoromethoxyphenyl 144 Br CH₂2-Iodo-3,5-dibromo-4-trifluoromethoxyphenyl 145 Br CH₂2-Fluoro-3,5-dibromo-4-trifluoromethoxyphenyl 146 Br CH₂3,5-Dimethyl-4-methoxyphenyl 147 Br CH₂2-Chloro-3,5-dimethyl-4-methoxyphenyl 148 Br CH₂2-Bromo-3,5-dimethyl-4-methoxyphenyl 149 Br CH₂2-Iodo-3,5-dimethyl-4-methoxyphenyl 150 Br CH₂2-Fluoro-3,5-dimethyl-4-methoxyphenyl 151 Br CH₂3,5-Dimethyl-4-bromophenyl 152 Br CH₂2-Chloro-3,5-dimethyl-4-bromophenyl 153 Br CH₂2,4-Dibromo-3,5-dimethylphenyl 154 Br CH₂2-Iodo-3,5-dimethyl-4-bromophenyl 155 Br CH₂2-Fluoro-3,5-dimethyl-4-bromophenyl 156 Br CH₂3,5-Dimethyl-4-chlorophenyl 157 Br CH₂ 2,4-Dichloro-3,5-dimethylphenyl158 Br CH₂ 2-Bromo-3,5-dimethyl-4-chlorophenyl 159 Br CH₂2-Iodo-3,5-dimethyl-4-chlorophenyl 160 1 Cl CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 161 2 Cl CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 162 Cl CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 163 Cl CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 164 Cl CH₂6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 165 Cl CH₂6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 166 Cl CH₂3,5-Dimethyl-4-bromopyridin-2-yl 167 Cl CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 168 Cl CH₂6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 169 Cl CH₂6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 170 Cl CH₂6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 171 Cl CH₂4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 172 Cl CH₂3,5-Dimethyl-4-chloropyridin-2-yl 173 Cl CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 174 Cl CH₂6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 175 Cl CH₂6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 176 Cl CH₂4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 177 Cl CH₂6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 178 Cl CH₂3,5-Dimethyl-4-iodopyridin-2-yl 179 Cl CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 180 Cl CH₂6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 181 Cl CH₂6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 182 Cl CH₂6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 183 Cl CH₂6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 184 Cl CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 185 Cl CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 186 Cl CH₂6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 187 Cl CH₂6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 188 Cl CH₂6-Chloro-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 189 Cl CH₂6-Bromo-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 190 Cl CH₂3,4,5-Trimethyl-pyridin-2-yl 191 Cl CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 192 Cl CH₂6-Bromo-3,4,5-trimethyl-pyridin-2-yl 193 Cl CH₂6-Chloro-3,4,5-trimethyl-pyridin-2-yl 194 Cl CH₂6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 195 Cl CH₂6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 196 Cl CH₂4,5,6-Trimethoxypyridin-2-yl 197 Cl CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 198 Cl CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 199 Cl CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 200 Cl CH₂3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 201 Cl CH₂3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 202 Cl CH₂3,4,5-Trimethoxy-pyridin-2-yl 203 Cl CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 204 Cl CH₂3-Bromo-3,4,5-trimethoxy-pyridin-2-yl 205 Cl CH₂3-Chloro-3,4,5-trimethoxy-pyridin-2-yl 206 Cl CH₂3-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 207 Cl CH₂3-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 208 Cl CH₂4,5,6-Trimethyl-pyridin-2-yl 209 Cl CH₂4,5,6-Trimethyl-1-oxypyridin-2-yl 210 Cl CH₂3-Bromo-4,5,6-trimethyl-pyridin-2-yl 211 Cl CH₂3-Chloro-4,5,6-trimethyl-pyridin-2-yl 212 Cl CH₂3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 213 Cl CH₂3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 214 Cl CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 215 Cl CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 216 Cl CH₂3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 217 Cl CH₂3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 218 Cl CH₂3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 219 Cl CH₂3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 220 Cl CH₂4-Bromo-5,6-dimethoxy-pyridin-2-yl 221 Cl CH₂4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 222 Cl CH₂3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 223 Cl CH₂3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 224 Cl CH₂3-Chloro-4-bromo-5,6-dimethoxy-1-oxypyridin-2-yl 225 Cl CH₂3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 226 Cl CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 227 Cl CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 228 Cl CH₂4,6-Dimethyl-5-bromopyridin-3-yl 229 Cl CH₂4,6-Dimethyl-5-chloropyridin-3-yl 230 Cl CH₂5,6-Dimethyl-4-bromopyridin-3-yl 231 Cl CH₂5,6-Dimethyl-4-chloropyridin-3-yl 232 Cl CH₂4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 233 Cl CH₂4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 234 Cl CH₂5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 235 Cl CH₂5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 236 Cl CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 237 Cl CH₂ 2,6-Dimethyl-pyridin-4-yl238 Cl CH₂ 2,3,6-Trimethyl-pyridin-4-yl 239 Cl CH₂2,3,6-Trimethoxy-pyridin-4-yl 240 Cl CH₂2,6-Dimethyl-3-bromopyridin-4-yl 241 Cl CH₂2,6-Dimethyl-3-chloropyridin-4-yl 242 Cl CH₂2,6-Dichloro-3-bromopyridin-4-yl 243 Cl CH₂2,6-Dibromo-3-chloropyridin-4-yl 244 Cl CH₂ 2,3,6-Trichloro-pyridin-4-yl245 Cl CH₂ 2,3,6-Tribromo-pyridin-4-yl 246 Cl CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 247 Cl CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 248 Cl CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 249 Cl CH₂2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 250 Cl CH₂2,6-Dimethyl-3-bromo-1-oxy-pyridin-4-yl 251 Cl CH₂2,6-Dimethyl-3-chloro-1-oxy-pyridin-4-yl 252 Cl CH₂2,6-Dichloro-3-bromo-1-oxy-pyridin-4-yl 253 Cl CH₂2,6-Dibromo-3-chloro-1-oxy-pyridin-4-yl 254 Cl CH₂2,3,6-Trichioro-1-oxy-pyridin-4-yl 255 Cl CH₂2,3,6-Tribromo-1-oxy-pyridin-4-yl 256 Cl CH₂4,6-Dimethyl-5-iodopyridin-3-yl 257 Cl CH₂5,6-Dimethyl-4-iodopyridin-3-yl 258 Cl CH₂ 4,5,6-Trichloropyridin-3-yl259 Cl CH₂ 4,5,6-Tribromopyridin-3-yl 260 Br CH₂3,5-Dimethyl-4-methoxypyridin-2-yl 261 Br CH₂3,5-Dimethyl-4-methoxy-1-oxypyridin-2-yl 262 Br CH₂6-Bromo-3,5-dimethyl-4-methoxypyridin-2-yl 263 Br CH₂6-Chloro-3,5-dimethyl-4-methoxypyridin-2-yl 264 Br CH₂6-Chloro-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 265 Br CH₂6-Bromo-3,5-dimethyl-4-methoxy-1-oxypyridin-2-yl 266 Br CH₂3,5-Dimethyl-4-bromopyridin-2-yl 267 Br CH₂3,5-Dimethyl-4-bromo-1-oxypyridin-2-yl 268 Br CH₂6-Bromo-3,5-dimethyl-4-bromopyridin-2-yl 269 Br CH₂6-Chloro-3,5-dimethyl-4-bromopyridin-2-yl 270 Br CH₂6-Chloro-3,5-dimethyl-4-bromo-1-oxypyridin-2-yl 271 Br CH₂4,6-Dibromo-3,5-dimethyl-1-oxypyridin-2-yl 272 Br CH₂3,5-Dimethyl-4-chloropyridin-2-yl 273 Br CH₂3,5-Dimethyl-4-chloro-1-oxypyridin-2-yl 274 Br CH₂6-Bromo-3,5-dimethyl-4-chloropyridin-2-yl 275 Br CH₂6-Chloro-3,5-dimethyl-4-chloropyridin-2-yl 276 Br CH₂4,6-Dichloro-3,5-dimethyl-1-oxypyridin-2-yl 277 Br CH₂6-Bromo-3,5-dimethyl-4-chloro-1-oxypyridin-2-yl 278 Br CH₂3,5-Dimethyl-4-iodopyridin-2-yl 279 Br CH₂3,5-Dimethyl-4-iodo-1-oxypyridin-2-yl 280 Br CH₂6-Bromo-3,5-dimethyl-4-iodopyridin-2-yl 281 Br CH₂6-Chloro-3,5-dimethyl-4-iodopyridin-2-yl 282 Br CH₂6-Chloro-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 283 Br CH₂6-Bromo-3,5-dimethyl-4-iodo-1-oxypyridin-2-yl 284 Br CH₂3,5-Dimethyl-4-thiomethyl-pyridin-2-yl 285 Br CH₂3,5-Dimethyl-4-thiomethyl-1-oxypyridin-2-yl 286 Br CH₂6-Bromo-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 287 Br CH₂6-Chloro-3,5-dimethyl-4-thiomethyl-pyridin-2-yl 288 Br CH₂6-Chloro-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 289 Br CH₂6-Bromo-3,5-dimethyl-4-thiomethyl-1-oxypyridin-2-yl 290 Br CH₂3,4,5-Trimethyl-pyridin-2-yl 291 Br CH₂3,4,5-Trimethyl-1-oxypyridin-2-yl 292 Br CH₂6-Bromo-3,4,5-trimethyl-pyridin-2-yl 293 Br CH₂6-Chloro-3,4,5-trimethyl-pyridin-2-yl 294 Br CH₂6-Chloro-3,4,5-trimethyl-1-oxypyridin-2-yl 295 Br CH₂6-Bromo-3,4,5-trimethyl-1-oxypyridin-2-yl 296 Br CH₂3,4,5-Trimethoxy-pyridin-2-yl 297 Br CH₂3,4,5-Trimethoxy-1-oxypyridin-2-yl 298 Br CH₂6-Bromo-3,4,5-trimethoxy-pyridin-2-yl 299 Br CH₂6-Chloro-3,4,5-trimethoxy-pyridin-2-yl 300 Br CH₂6-Chloro-3,4,5-trimethoxy-1-oxypyridin-2-yl 301 Br CH₂6-Bromo-3,4,5-trimethoxy-1-oxypyridin-2-yl 302 Br CH₂4,5,6-Trimethoxypyridin-2-yl 303 Br CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 304 Br CH₂3-Bromo-4,5,6-trimethoxypyridin-2-yl 305 Br CH₂3-Chloro-4,5,6-trimethoxypyridin-2-yl 306 Br CH₂3-Chloro-4,5,6-trimethoxy-1-oxypyridin-2-yl 307 Br CH₂3-Bromo-4,5,6-trimethoxy-1-oxypyridin-2-yl 308 Br CH₂4,5,6-Trimethoxypyridin-2-yl 309 Br CH₂4,5,6-Trimethoxy-1-oxypyridin-2-yl 310 Br CH₂3-Bromo-4,5,6-trimethyl-pyridin-2-yl 311 Br CH₂3-Chloro-4,5,6-trimethyl-pyridin-2-yl 312 Br CH₂3-Chloro-4,5,6-trimethyl-1-oxypyridin-2-yl 313 Br CH₂3-Bromo-4,5,6-trimethyl-1-oxypyridin-2-yl 314 Br CH₂4,6-Dimethyl-5-methoxy-pyridin-2-yl 315 Br CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-2-yl 316 Br CH₂3-Bromo-4,6-dimethyl-5-methoxy-pyridin-2-yl 317 Br CH₂3-Chloro-4,6-dimethyl-5-methoxy-pyridin-2-yl 318 Br CH₂3-Chloro-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 319 Br CH₂3-Bromo-4,6-dimethyl-5-methoxy-1-oxypyridin-2-yl 320 Br CH₂4-Bromo-5,6-dimethoxy-pyridin-2-yl 321 Br CH₂4-Bromo-5,6-dimethoxy-1-oxypyridin-2-yl 322 Br CH₂3,4-Dibromo-5,6-dimethoxy-pyridin-2-yl 323 Br CH₂3-Chloro-4-bromo-5,6-dimethoxy-pyridin-2-yl 324 Br CH₂3-Chloro-4-bromo-5,6-dimethoxy-I-oxypyridin-2-yl 325 Br CH₂3,4-Dibromo-5,6-dimethoxy-1-oxypyridin-2-yl 326 Br CH₂4,6-Dimethyl-5-methoxypyridin-3-yl 327 Br CH₂4,6-Dimethyl-5-methoxy-1-oxypyridin-3-yl 328 Br CH₂4,6-Dimethyl-5-bromopyridin-3-yl 329 Br CH₂4,6-Dimethyl-5-chloropyridin-3-yl 330 Br CH₂5,6-Dimethyl-4-bromopyridin-3-yl 331 Br CH₂5,6-Dimethyl-4-chloropyridin-3-yl 332 Br CH₂4,6-Dimethyl-5-bromo-1-oxypyridin-pyridin-3-yl 333 Br CH₂4,6-Dimethyl-5-chloro-1-oxypyridin-pyridin-3-yl 334 Br CH₂5,6-Dimethyl-4-bromo-1-oxypyridin-pyridin-3-yl 335 Br CH₂5,6-Dimethyl-4-chloro-1-oxypyridin-pyridin-3-yl 336 Br CH₂2,6-Dimethyl-3-methoxypyridin-4-yl 337 Br CH₂ 2,6-Dimethyl-pyridin-4-yl338 Br CH₂ 2,3,6-Trimethyl-pyridin-4-yl 339 Br CH₂2,3,6-Trimethoxy-pyridin-4-yl 340 Br CH₂2,6-Dimethyl-3-bromopyridin-4-yl 341 Br CH₂2,6-Dimethyl-3-chloropyridin-4-yl 342 Br CH₂2,6-Dichloro-3-bromopyridin-4-yl 343 Br CH₂2,6-Dibromo-3-chloropyridin-4-yl 344 Br CH₂ 2,3,6-Trichloro-pyridin-4-yl345 Br CH₂ 2,3,6-Tribromo-pyridin-4-yl 346 Br CH₂2,6-Dimethyl-3-methoxy-1-oxy-pyridin-4-yl 347 Br CH₂2,6-Dimethyl-1-oxy-pyridin-4-yl 348 Br CH₂2,3,6-Trimethyl-1-oxy-pyridin-4-yl 349 Br CH₂2,3,6-Trimethoxy-1-oxy-pyridin-4-yl 350 Br CH₂2,6-Dimethyl-3-bromo-1-oxy-pyridin-4-yl 351 Br CH₂2,6-Dimethyl-3-chloro-1-oxy-pyridin-4-yl 352 Br CH₂2,6-Dichloro-3-bromo-1-oxy-pyridin-4-yl 353 Br CH₂2,6-Dibromo-3-chloro-1-oxy-pyridin-4-yl 354 Br CH₂2,3,6-Trichloro-1-oxy-pyridin-4-yl 355 Br CH₂2,3,6-Tribromo-1-oxy-pyridin-4-yl 356 Br CH₂4,6-Dimethyl-5-iodopyridin-3-yl 357 Br CH₂5,6-Dimethyl-4-iodopyridin-3-yl 358 Br CH₂ 4,5,6-Trichloropyridin-3-yl359 Br CH₂ 4,5,6-Tribromopyridin-3-yl 360 Cl CH₂4,5,6-Trimethoxy-3-chloropyridin-2-yl 361 Br CH₂4,5,6-Trimethoxy-3-chloropyridin-2-yl 362 Cl CH₂4,5,6-Trimethoxy-3-bromopyridin-2-yl 363 Br CH₂4,5,6-Trimethoxy-3-bromopyridin-2-yl 364 Cl CH₂4,5,6-Trimethoxy-pyridin-3-yl 365 Cl CH₂4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 366 Cl CH₂2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 367 Cl CH₂2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 368 Cl CH₂2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 369 Cl CH₂2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 370 Cl CH₂4,5,6-Trimethyl-pyridin-3-yl 371 Cl CH₂4,5,6-Trimethyl-1-oxy-pyridin-3-yl 372 Cl CH₂2-Bromo-4,5,6-trimethyl-pyridin-3-yl 373 Cl CH₂2-Chloro-4,5,6-trimethyl-pyridin-3-yl 374 Cl CH₂2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 375 Cl CH₂2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-yl 376 Cl CH₂2-Iodo-4,5,6-trimethyl-pyridin-3-yl 377 Cl CH₂2-Iodo-4,5,6-trimethyl-pyridin-3-yl 378 Br CH₂4,5,6-Trimethoxy-pyridin-3-yl 379 Br CH₂4,5,6-Trimethoxy-1-oxy-pyridin-3-yl 380 Br CH₂2-Bromo-4,5,6-trimethoxy-pyridin-3-yl 381 Br CH₂2-Chloro-4,5,6-trimethoxy-pyridin-3-yl 382 Br CH₂2-Chloro-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 383 Br CH₂2-Bromo-4,5,6-trimethoxy-1-oxy-pyridin-3-yl 384 Br CH₂4,5,6-Trimethyl-pyridin-3-yl 385 Br CH₂4,5,6-Trimethyl-1-oxy-pyridin-3-yl 386 Br CH₂2-Bromo-4,5,6-trimethyl-pyridin-3-yl 387 Br CH₂2-Chloro-4,5,6-trimethyl-pyridin-3-yl 388 Br CH₂2-Chloro-4,5,6-trimethyl-1-oxy-pyridin-3-yl 389 Br CH₂2-Bromo-4,5,6-trimethyl-1-oxy-pyridin-3-ylCompounds of interest in Table 1 are compounds 2, 3, 13, 82, 83, 162,163, 168, 169, 174, 175, 180, 181, 186, 187, 192, 193, 198, 199, 204,205, 210, 211, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 250,251, 262, 263, 268, 269, 274, 275, 280, 281, 286, 287, 292, 293, 298,299, 304, 305, 310, 311, 316, 317, 328, 329, 338, 372, 373, 380 and 381with selected compounds being 162, 163, 168, 169, 174, 175, 180, 181,186, 187, 192, 193, 198, 199, 204, 205, 228, 229, 262, 263, 268, 269,274, 275, 280, 281, 286, 287, 292, 293, 316, 317, 328, and 329.III. Synthesis of the Compounds of the Invention

The compounds of Formula I (see Scheme 1) of the present invention maybe synthesized by various methods known in the art, including thosedescribed in, for example, Parkanyi, J. Heterocyl. Chem., 1990, 27(5),1409-13; Beauchamp, U.S. Pat. No. 4,714,701, 1987; Meier, U.S. Pat. No.5,204,353, 1993. Gillespie, WO 02/055083; Peterson, J. Med. Chem., 1990,33(4), 1214-19. The general synthetic strategy is outlined in Scheme 1and consists of three parts: (1) constructing the bicyclic system,starting from either a pyrimidine or a 1,2,3-triazole, (2) appending theR⁵—R⁴-group, and (3) further elaborating the ring systems.

Importantly, one skilled in the art will recognize that the sequence ofevents is not necessarily (1)-(2)-(3), and that these events may beinterchanged, provided there be no incompatibility between the reagentsand the functional groups specific to the point in case.

The starting material and/or the intermediates of, e.g., Formulae 1, 2or/and 4 can exist in tautomeric forms, and both forms areindiscriminately described in the specification.

From Pyrimidines:

Method 1

Compounds of Formula I can be prepared from the commercially availablesubstituted pyrimidines compounds of Formula 1 where R⁹ is OH orhalogen, R¹⁰ is amino or protected amino or any group that can beconverted to amino, such as SMe, R¹¹ is H or NO₂, R¹² is Cl, (see Scheme2) by treating with an excess halogenating agent such as POCl₃, oxalylchloride, or PCl₅, and a formulating agent such as DMF to give compoundsof Formula 1 where R⁹ is halogen, and R¹² is halogen, followed byhalogen displacement with an nucleophile, such as NH₂—R⁴—R⁵, in solventssuch as EtOH, tBuOH etc. in presence of organic bases such as Et₃N,(i-Pr)₂NEt etc. to yield a compound of Formula 2. Formula 2, where R¹¹is NO₂, may then be reduced with zinc and formic acid or sodiumdithionite to give compounds of Formula 2, where R¹¹ is NH₂, see Dempcy,U.S. Publication No. 2003/0078413 A1. Compounds of Formula I can then beprepared by diazotization with an alkali metal nitrite such as NaNO₂ ininorganic acids such as HCl, followed by in situ cyclization. (SeeBeauchamp, U.S. Pat. No. 4,714,701; Meier, U.S. Pat. No. 5,204,353)These compounds of Formula I can be further modified as necessary.

Formula 2, where R¹¹ is H, can be treated with diazonium salts such as4-chloroaniline diazonium salt prepared from 4-chloroaniline and NaNO₂inorganic acids such as HCl to give pyrimidine 5-azo-analog, that can bereduced with zinc dust in EtOH/AcOH (1:1) solution to give compounds ofFormula 2, where R¹¹ is NH₂ (see Meier, U.S. Pat. No. 5,204,353).

Method 2

Compounds of Formula I also can be prepared from the commerciallyavailable substituted diamino pyrimidines compounds of Formula 1 whereR⁹ is OH or halogen, R¹⁰ is amino or protected amino or any group thatcan be converted to amino, such as SMe, R¹¹ & R¹² are NH₂, (see Scheme3>following the diazotization method described earlier in Method 1 togive compounds of Formula 4. Formula 4 can be alkylated in the presenceof a base such as K₂CO₃, NaH, Cs₂CO₃, DBU etc. with/without the presenceof halide such as NaI, KI, (Bu)₃NI etc., and in a polar solvent such asDMF, THF, DMSO etc. using electrophiles such as L¹-R⁴—R⁵ where L¹ is aleaving group. Leaving groups include but are not limited to, e.g.,halogen, triflate, tosylate, mesylate etc. (See Kasibhatla, WO03/037860) Compounds of Formula I can also be prepared from compounds ofFormula 4 using Mitsunobu alkylation conditions using L¹-R⁴—R⁵ where L¹is hydroxyl. (See Kozai, Chem. Pharm. Bull., 1999, 47(4), 574-575).

Method 3

From Triazole:

Compounds of Formula I can also be prepared from a substituted triazoleas shown in Scheme 4. Accordingly, compounds of Formula 3, wherein R¹⁴is NH₂, R¹³ is C(O)NH₂ and R¹⁵ is H (commercially available), can bealkylated in the presence of a base such as KOH, NaOH, K₂CO₃, NaH,Cs₂CO₃, DBU etc. with/without the presence of halide such as NaI, KI,(Bu)₃NI etc., and in a polar solvent such as DMF, THF, DMSO etc. usingelectrophiles such as L¹-R⁴—R⁵ where L¹ is a leaving group. Leavinggroups include but are not limited to, e.g., halogen, triflate,tosylate, mesylate etc. to give compounds of Formula 6. The ring closurecan be achieved using many methods reported in the literature (Alhede,J. Org. Chem., 1991, 2139 and references cited therein) to givecompounds of Formula I, wherein R¹ is OH. These compounds can beconverted to the compounds of Formula I, wherein R¹ is Cl, using POCl₃as described earlier. Alternately, we can also construct from Formula 3,wherein R¹⁴ is —OH or halide, R¹³ is —C(O)OEt by reacting with guanidinehydrochloride as described in Chowdhury, J. Med. Chem. 1999, 42, 4300.

Preparation of Electrophiles L¹-R⁴—R⁵ wherein L₁ is a Leaving Group andof Nucleophiles NH₂—R⁴—R⁵.Synthesis of Benzyl Type Electrophile:

The electrophiles can be prepared from the substituted benzenederivatives using various methods reported in the literature, see JerryMarch, Advanced Organic Chemistry, 4th edition; Larock, ComprehensiveOrganic Transformations, 1989, VCH, New York. For example, compoundswhere L¹ is —Br can be prepared by reduction followed by halogenation ofthe benzoic acid or aldehyde derivatives. These benzyl derivatives canalso be prepared by benzylic oxidation or benzylic halogenation. Furthermodification of the benzyl ring can be done before or after thetriazolopurine alkylation step; for example halogenation was done bothways.

Synthesis of Pyridyl Methyl Type Electrophile:

These compounds can be prepared from many methods reported in theliterature. Morisawa et al. J. Med. Chem. 1974, 17, 1083; Klaus, W. etal. J. Med. Chem. 1992, 35, 438; Abramovitch, R. A.; Smith, E. M.“Pyridine-1-oxide in Pyridine and its Derivatives” in The Chemistry ofHeterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; JohnWieley, New York, 1974, Pt. 2, pp 1-261; Jeromin, G. E. et al. Chem.Ber. 1987, 120, 649. Blanz, E. J., et al. J. Med. Chem. 1970, 13, 1124;Smith, Kline and French, EP 0184322, 1986; Abblard, J. et al. Bull. Soc.Chim. Fr. 1972, 2466; Fisher, B. E. et al. “The Structure of Isomaltol.”J Org Chem. 1964, 29, 776. De Cat, A. et al. Bull. Soc. Chim. Belg.1965, 74, 270; Looker, J. H. et al. J. Org. Chem. 1979, 44, 3407.Ackerman, J. F. Ph.D. Dissertation, University of Notre Dame, June,1949. These methods can be applied to the synthesis of quinoline, andisoquinolines type compounds.

The compound R⁴—R⁵—NH₂ is obtained by treating. R⁴—R⁵-L¹ with ammonia attemperatures of 20-160° C. in a pressure vessel, wherein L¹ is leavinggroup such as chloride, bromide, tosylate, mesylate etc. using ammonia,or with sodium azide followed by hydrogenation.

Further Elaboration of the Ring Systems.

These modifications can be done at any stage depending upon theincompatibility of the functional groups present.

Functional Group Interconversions of R¹:

Compounds of Formula I, wherein R¹ is OH, can be converted to halidesusing standard conditions POCl₃, POBr₃ etc. with/without a base such asEt₃N,N,N-dimethylaniline, (i-Pr)₂NEt etc. and with/without a catalystsuch as BnEt₃N⁺Cl⁻, in polar solvents such as CH₃CN, CH₂Cl₂ etc. Relatedmethods include, but are not limited to, SOCl₂/DMF (M. J. Robins, Can.J. Chem. 1973, 12, 3161), PPh₃/CCl₄ (L. De Napoli, J. Chem. Soc. PerkinTrans 1, 1994, 923), HMPT/CCl₄ or HMPT/NBS (E. A. Veliz, TetrahedronLett, 2000, 41, 1695) or PPh₃/I₂ (X. Lin, Org. Letters, 2000, 2, 3497).

Compounds of Formula I, wherein R¹ is NH₂, can be converted to halidesby a Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of anitrosylating agent (NaNO₂/H+, NOBF₄, RONO) and a halogen donor (BF₄ ⁻,CuX₂, SbX₃, where X is halogen).

Compounds of Formula I, wherein R¹ is alkyl can be prepared fromcompounds of Formula 4 where R¹ is halogen and trialkyl aluminum ordialkyl zinc (A. Holy, J. Med. Chem. 1999, 42, 2064).

Compounds of Formula I, wherein R¹ is a halide can be converted tocompounds wherein R¹ is NH₂, OH, SH, OR⁸, SR⁸ with standard reagents,e.g. NH₃, NaOH, thiourea, R⁸O⁻, R⁸S⁻, with or without a catalyst (e.g.Pd, Ni, Cu, Lewis acid, H⁺) (e.g. B. G. Ugarkar, J. Med. Chem. 2000, 43,2883-2893 and 2894-2905).

Compounds of Formula I, wherein R¹ is halogen or another leaving groupcan be treated with ammonia to provide compounds of Formula I wherein R¹is NH₂ (F. Seela, Liebigs. Ann. Chem. 1985, 315).

Functional Group Interconversions of R²:

Compounds of Formula I, wherein R² is NH₂ can be temporarily protected,e.g. as an amide (Ac₂O, PivCl), a carbamate (tBoc)₂O) or amidine(DMF-DMA).

Compounds of Formula I, wherein R² is NH₂ can be converted to halides bya Balz-Schiemann (F) or Sandmeyer reaction (Cl, Br, I) by means of anitrosylating agent (NaNO₂/H+, NOBF₄, RONO) and a halogen donor (BF4⁻,CuX₂, SbX₃).

Compounds of Formula I, wherein R² is a halide can be converted tocompounds wherein R² is NH₂, OH, SH, OR⁸, SR⁸ with standard reagents,e.g. NH₃, NaOH, thiourea, R⁸O⁻, R⁸S⁻, with or without a catalyst (e.g.Pd, Ni, Cu, Lewis acid, H⁺).

Compounds of Formula I, wherein R² is SH can be converted to halides(Br₂). They can also be oxidized (e.g. H₂O₂) and treated with ammonia togive a NH₂ group (S. M. Bennett, J. Med Chem. 1990, 33, 2162).

Compounds of Formula I, wherein R² is a sulfide, e.g. MeS—, can beconverted to a sulfone, e.g., MeSO₂ ⁻, and displaced with a nucleophile,e.g. NH₃ or NH₂—NH₂, N₃ ⁻, CN⁻.

Compounds of Formula I, wherein R² is a sulfide, e.g. MeS—, can beconverted to a sulfone, e.g., MeSO₂ ⁻, and displaced with a nucleophile,e.g., NH₃ or NH₂-NH₂, N₃ ⁻, CN⁻.

Further Elaboration of R⁵:

R⁵, especially when it is aryl or heteroaryl, can be further modified asneeded, for example by halogenation, nitration, palladium coupling ofhalogen, Friedel-Crafts alkylation/acylation, etc. or thesemodifications can also be done before alkylation, see Jerry March,Advanced Organic Chemistry. The heteroaromatic rings can also beoxidized to their corresponding N-oxides using various oxidizing agentssuch as H₂O₂, 03, MCPBA etc. in polar solvents such as CH₂Cl₂, CHCl₃,CF₃COOH etc. See Jerry March, Advanced Organic Chemistry, 4th edition,Chapter 19. Examples of modifications are suggested in Scheme 5.

Also, if R⁵ is for instance a pyridine, it can be converted to a N-oxideeither before or after alkylation.

IV. Pharmaceutical Compositions, Dosing, and Modes of Administration

The present invention is directed to the clinical use of theheterocyclics, in particular, the triazolopyrimidine and their relatedanalogs of Formulae A and I, and their polymorphs, solvates, esters,tautomers, enantiomers, pharmaceutically acceptable salts and prodrugsthereof, for use in treatment or prevention of diseases that areHSP90-dependent. For example, a disorder such as inflammatory diseases,infections, autoimmune disorders, stroke, ischemia, cardiac disorder,neurological disorders, fibrogenetic disorders, proliferative disorders,tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases,and malignant disease. The fibrogenetic disorders include but are notlimited to scleroderma, polymyositis, systemic lupus, rheumatoidarthritis, liver cirrhosis, keloid formation, interstitial nephritis andpulmonary fibrosis.

The present invention features pharmaceutical compositions comprisingthe compound of Formulae A and I, or a polymorph, solvate, ester,tautomer, pharmaceutically acceptable salt thereof, or prodrug thereof,of any of the preceding aspect and embodiments and one or morepharmaceutical excipients. Those of ordinary skill in the art arefamiliar with formulation and administration techniques that can beemployed with the compounds and methods of the invention, e.g., asdiscussed in Goodman and Gilman, The Pharmacological Basis ofTherapeutics, (current edition), Pergamon; and Remington's,Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton,Pa.

The compounds utilized in the methods of the instant invention may beadministered either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practices. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

For example, the therapeutic or pharmaceutical compositions of theinvention can be administered locally to the area in need of treatment.This may be achieved by, for example, but not limited to, local infusionduring surgery, topical application, e.g., cream, ointment, injection,catheter, or implant, said implant made, e.g., out of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. The administration can also be by directinjection at the site (or former site) of a tumor or neoplastic orpre-neoplastic tissue.

Still further, the compounds or compositions of the invention can bedelivered in a vesicle, e.g., a liposome (see, for example, Langer,Science 1990, 249, 1527-1533; Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer, Lopez-Bernstein and Fidler, Ed., Liss,N.Y., pp. 353-365, 1989).

The compounds and pharmaceutical compositions used in the methods of thepresent invention can also be delivered in a controlled release system.In one embodiment, a pump may be used (see, Sefton, 1987, CRC Crit. Ref.Biomed. Eng. 14:201; Buchwald et al. Surgery, 1980, 88, 507; Saudek etal. N. Engl. J. Med. 1989, 321, (574). Additionally, a controlledrelease system can be placed in proximity of the therapeutic target.(See, Goodson, Medical Applications of Controlled Release, 1984, 2,115-138).

The pharmaceutical compositions used in the methods of the instantinvention can also contain the active ingredient in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions, and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,such as microcrystalline cellulose, sodium crosscarmellose, corn starch,or alginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be un-coatedor coated by known techniques to mask the taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, or cellulose acetate butyrate may be employed as appropriate.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachisd oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The compounds and pharmaceutical compositions used in the methods of theinstant invention may also be in the form of an oil-in-water emulsions.The oily phase may be a vegetable oil, for example olive oil or arachisoil, or a mineral oil, for example liquid paraffin or mixtures of these.Suitable emulsifying agents may be naturally-occurring phosphatides, forexample soy bean lecithin, and esters or partial esters derived fromfatty acids and hexitol anhydrides, for example sorbitan monooleate, andcondensation products of the said partial esters with ethylene oxide,for example polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening agents, flavoring agents, preservatives andantioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solution. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulsion.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

The compounds of the present invention used in the methods of thepresent invention may also be administered in the form of suppositoriesfor rectal administration of the drug. These compositions can beprepared by mixing the inhibitors with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing a compound or composition of the invention can be used.As used herein, topical application can include mouth washes andgargles.

The compounds used in the methods of the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles and delivery devices, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The methods, compounds and compositions of the instant invention mayalso be used in conjunction with other well known therapeutic agentsthat are selected for their particular usefulness against the conditionthat is being treated. For example, the instant compounds may be usefulin combination with known anti-cancer and cytotoxic agents. Further, theinstant methods and compounds may also be useful in combination withother inhibitors of parts of the signaling pathway that links cellsurface growth factor receptors to nuclear signals initiating cellularproliferation.

The methods of the present invention may also be useful with otheragents that inhibit angiogenesis and thereby inhibit the growth andinvasiveness of tumor cells, including, but not limited to VEGF receptorinhibitors, including ribozymes and antisense targeted to VEGFreceptors, angiostatin and endostatin.

Examples of antineoplastic agents that can be used in combination withthe compounds and methods of the present invention include, in general,and as appropriate, alkylating agents, anti-metabolites,epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents and haematopoietic growthfactors. Exemplary classes of antineoplastic include the anthracyclines,vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones,discodermolides, pteridines, diynenes and podophyllotoxins. Particularlyuseful members of those classes include, for example, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin orpodo-phyllotoxin derivatives such as etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, paclitaxel and the like. Other useful antineoplastic agentsinclude estramustine, carboplatin, cyclophosphamide, bleomycin,gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa,cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase,camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

When a compound or composition of the invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer, for example,breast cancer. Administration typically occurs in an amount of betweenabout 0.01 mg/kg of body weight to about 100 mg/kg of body weight perday (administered in single or divided doses), more preferably at leastabout 0.1 mg/kg of body weight per day. A particular therapeutic dosagecan include, e.g., from about 0.01 mg to about 1000 mg of compound, andpreferably includes, e.g., from about 1 mg to about 1000 mg. Thequantity of active compound in a unit dose of preparation may be variedor adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to300 mg, more preferably 10 mg to 200 mg, according to the particularapplication. The amount administered will vary depending on theparticular IC₅₀ value of the compound used and the judgment of theattending clinician taking into consideration factors such as health,weight, and age. In combinational applications in which the compound isnot the sole active ingredient, it may be possible to administer lesseramounts of compound and still have therapeutic or prophylactic effect.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small amounts until the optimumeffect under the circumstances is reached. For convenience, the totaldaily dosage may be divided and administered in portions during the dayif desired.

The amount and frequency of administration of the compounds andcompositions of the present invention used in the methods of the presentinvention, and if applicable other chemotherapeutic agents and/orradiation therapy, will be regulated according to the judgment of theattending clinician (physician) considering such factors as age,condition and size of the patient as well as severity of the diseasebeing treated.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

Also, in general, the compounds of the invention need not beadministered in the same pharmaceutical composition as achemotherapeutic agent, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the compounds/compositions may be administered orally togenerate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of compound (and where appropriate,chemotherapeutic agent and/or radiation) will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol.

The compounds/compositions of the invention (and where appropriatechemotherapeutic agent and/or radiation) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the patient, and theactual choice of chemotherapeutic agent and/or radiation to beadministered in conjunction (i.e., within a single treatment protocol)with the compound/composition.

In combinational applications and uses, the compound/composition and thechemotherapeutic agent and/or radiation need not be administeredsimultaneously or essentially simultaneously, and the initial order ofadministration of the compound/composition, and the chemotherapeuticagent and/or radiation, may not be important. Thus, thecompounds/compositions of the invention may be administered firstfollowed by the administration of the chemotherapeutic agent and/orradiation; or the chemotherapeutic agent and/or radiation may beadministered first followed by the administration of thecompounds/compositions of the invention. This alternate administrationmay be repeated during a single treatment protocol. The determination ofthe order of administration, and the number of repetitions ofadministration of each therapeutic agent during a treatment protocol, iswell within the knowledge of the skilled physician after evaluation ofthe disease being treated and the condition of the patient. For example,the chemotherapeutic agent and/or radiation may be administered first,especially if it is a cytotoxic agent, and then the treatment continuedwith the administration of the compounds/compositions of the inventionfollowed, where determined advantageous, by the administration of thechemotherapeutic agent and/or radiation, and so on until the treatmentprotocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of acompound/composition for treatment according to the individual patient'sneeds, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

V. Assays for Determining HSP90 Binding and Downstream Effect

A variety of in vitro and in vivo assays are available to test theeffect of the compounds of the invention on HSP90. HSP90 competitivebinding assays and functional assays can be performed as known in theart substituting in the compounds of the invention. Chiosis et al.Chemistry & Biology 2001, 8, 289-299, describe some of the known ways inwhich this can be done. For example, competition binding assays using,e.g., geldanamycin or 17-AAG as a competitive binding inhibitor of HSP90can be used to determine relative HSP90 affinity of the compounds of theinvention by immobilizing the compound of interest or other competitiveinhibitor on a gel or solid matrix, preincubating HSP90 with the otherinhibitor, passing the preincubated mix over the gel or matrix, and thenmeasuring the amount of HSP90 that retains or does not retain on the gelor matrix.

Downstream effects can also be evaluated based on the known effect ofHSP90 inhibition on function and stability of various steroid receptorsand signaling proteins including, e.g., Rafl and HER2. Compounds of thepresent invention induce dose-dependent degradation of these molecules,which can be measured using standard techniques. Inhibition of HSP90also results in up-regulation of HSP90 and related chaperone proteinsthat can similarly be measured. Antiproliferative activity on variouscancer cell lines can also be measured, as can morphological andfunctional differentiation related to HSP90 inhibition.

Many different types of methods are known in the art for determiningprotein concentrations and measuring or predicting the level of proteinswithin cells and in fluid samples. Indirect techniques include nucleicacid hybridization and amplification using, e.g., polymerase chainreaction (PCR). These techniques are known to the person of skill andare discussed, e.g., in Sambrook, Fritsch & Maniatis Molecular Cloning:A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, Cold SpringHarbor, N.Y., 1989; Ausubel, et al. Current Protocols in MolecularBiology, John Wiley & Sons, NY, 1994, and, as specifically applied tothe quantification, detection, and relative activity of HER2/Neu inpatient samples, e.g., in U.S. Pat. Nos. 4,699,877, 4,918,162,4,968,603, and 5,846,749. A brief discussion of two generic techniquesthat can be used follows.

The determination of whether cells overexpress or contain elevatedlevels of HER2 can be determined using well known antibody techniquessuch as immunoblotting, radioimmunoassays, western blotting,immunoprecipitation, enzyme-linked immunosorbant assays (ELISA), andderivative techniques that make use of antibodies directed against HER2.As an example, HER2 expression in breast cancer cells can be determinedwith the use of an immunohistochemical assay, such as the Dako Hercep™test (Dako Corp., Carpinteria, Calif.). The Hercep™ test is an antibodystaining assay designed to detect HER2 overexpression in tumor tissuespecimens. This particular assay grades HER2 expression into fourlevels: 0, 1, 2, and 3, with level 3 representing the highest level ofHER2 expression. Accurate quantitation can be enhanced by employing anAutomated Cellular Imaging System (ACIS) as described, e.g., by Press,M. et al. Modern Pathology 2000, 13, 225A.

Antibodies, polyclonal or monoclonal, can be purchased from a variety ofcommercial suppliers, or may be manufactured using well-known methods,e.g., as described in Harlow et al. Antibodies: A Laboratory Manual, 2nded; Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1988.

HER2 overexpression can also be determined at the nucleic acid levelsince there is a reported high correlation between overexpression of theHER2 protein and amplification of the gene that codes for it. One way totest this is by using RT-PCR. The genomic and cDNA sequences for HER2are known. Specific DNA primers can be generated using standard,well-known techniques, and can then be used to amplify template alreadypresent in the cell. An example of this is described in Kurokawa, H. etal. Cancer Res. 2000, 60, 5887-5894. PCR can be standardized such thatquantitative differences are observed as between normal and abnormalcells, e.g., cancerous and noncancerous cells. Well known methodsemploying, e.g., densitometry, can be used to quantitate and/or comparenucleic acid levels amplified using PCR.

Similarly, fluorescent in situ hybridization (FISH) assays and otherassays can be used, e.g., Northern and/or Southern blotting. These relyon nucleic acid hybridization between the HER2 gene or mRNA and acorresponding nucleic acid probe that can be designed in the same or asimilar way as for PCR primers, above. See, e.g., Mitchell M S, andPress M. F. Oncol., Suppl. 1999, 12, 108-116. For FISH, this nucleicacid probe can be conjugated to a fluorescent molecule, e.g.,fluorescein and/or rhodamine, that preferably does not interfere withhybridization, and which fluorescence can later be measured followinghybridization. See, e.g., Kurokawa, H et al, Cancer Res. 2000, 60,5887-5894 (describing a specific nucleic acid probe having sequence5′-FAM-NucleicAcid-TAMRA-p-3′ sequence). ACIS-based approaches asdescribed above can be employed to make the assay more quantitative (dela Torre-Bueno, J., et al. Modern Pathology 2000, 13, 221A).

Immuno and nucleic acid detection can also be directed against proteinsother than HSP90 and HER2, which proteins are nevertheless affected inresponse to HSP90 inhibition.

The following examples are offered by way of illustration only and arenot intended to be limiting of the full scope and spirit of theinvention.

EXAMPLES

I. Materials and Methods

The chemical reagents used to create the novel products of the inventionbelow are all available commercially, e.g., from Aldrich Chemical Co.,Milwaukee, Wis., USA. Otherwise their preparation is facile and known toone of ordinary skill in the art, or it is referenced or describedherein.

The final compounds were usually purified by preparative TLC (silica gel60 Å, Whatman Partisil PK6F) or flash chromatography (silica gel 60 Å,EMD Chemicals) using EtOAc/hexane or MeOH/CH₂Cl₂ as eluents. Rf's weremeasured using silica gel TLC plates (silica gel 60 Å, EMD Chemicals).Analytical HPLC chromatograms were obtained using a C18 column (AgilentZorbax 300SB-C18; 5 microns; 4.6 mm×150 mm). A gradient was appliedbetween solvent A (0.1% TFA in H₂O) and solvent B (0.5% TFA in CH₃CN)increasing the proportion of A linearly from 5% (t=0) to 100% (t=7.00min), with a constant flow rate of 1 mL/min. The samples were diluted totypically 0.1-1 mg/mL in MeOH or CH₃CN and the injection volumes weretypically 10 μL. The column was not heated, and UV detection waseffected at 254 nm. ¹H-NMR spectra were recorded on a Bruker Avance 400MHz spectrometer.

The chemical names were generated using the Beilstein Autonom 2.1software.II. General Procedures

General Procedure 1: Displacement of Chlorine with Amines

Ref: Helv. Chim Acta. 1986, 69, 1602-1613; U.S. Pat. No. 5,917,042

A mixture of benzylamine derivative or aminomethylpyridine derivative(5.88 mmole, 2.1 equivalents), triethylamine (1 ml, 7.2 mmole) and4,6-dichloro-pyrimidine-2,5-diamine (0.5 g, 2.8 mmole), was refluxed inn-BuOH or ethanol (10 mLs) for 3 to 18 hours. The mixture was cooled toroom temperature and was extracted with CH₂Cl₂. The organic layer waswashed with water and dried with MgSO₄ to afford the crude product. Thepyridinyl derivatives were purified by chromatography (100% EtOAc-10%MeOH/EtOAc), whereas the benzyl derivatives were used without furtherpurification.

General Procedure 2: Cyclization to Form Triazolopyrimidine Ring System

To a solution of 6-chloro-N⁴-benzyl-pyrimidine-2,4,5-triaminederivatives or 6-chloro-N⁴-pyridin-2-ylmethyl-pyrimidine-2,4,5-triaminederivatives (0.57 mmole) in 25% HOAc/H₂O, an aqueous solution of NaNO₂(1.2 equivalents, 1 mL) was added dropwise at 0° C. The reaction mixturewas stirred for 15 minutes at room temperature and filtered the crudeproduct and purified by column chromatography using 75%EtOAc/Hexanes-100% EtOAc.

General Procedure 3: Aromatic Ring Halogenation

A mixture of7-chloro-3-benzyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylaminederivatives (0.57 mmole) and NCS(N-chlorosuccinimide) or NBS(N-bromosuccinimide) or NIS (N⁴-iodosuccinimide) (1.5 equivalents) in 10mLs HOAc was stirred at 50° C. for 1 to 15 hours to afford the crudecorresponding halogenated product which was purified by chromatography(50-75% EtOAc/Hexanes).

General Procedure 4: N-oxide Formation

A solution of the pyridine derivative (1 mmol) in dichloromethane orchloroform (5 mL) was cooled by means of an ice-bath, treated withm-CPBA (1.1 to 3 mmol) in three portions, and allowed to warm to r.t.The mixture was extracted with dichloromethane and washed with aqueousNaOH, followed by water. Drying (Na₂SO₄) and concentration afforded thepyridine N-oxide.

Example 17-Chloro-3-(4-methoxy-3,5-dimethylpyridin-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: Synthesis of 2-aminomethyl-4-methoxy-3,5-dimethylpyridine

A solution of 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine HCl(Aldrich 3.7 g, 16.6 mmole) in 7N NH₃/MeOH (Aldrich, 200 mLs) wasrefluxed in a steel bomb for 15 hours. Removed the solvent under reducedpressure, the residue was taken into 5% MeOH/CH₂Cl₂ and filtering itthrough a thin layer of silica gel afforded the product at 76% yield.HPLC RT was 2.850 min. ¹HNMR (CDCl₃) δ 8.18 (s, 1H), 4.32 (s, 2H), 3.76(s, 3H), 2.23 (s, 3H), 2.18 (s, 3H).

Step 2: Synthesis of6-chloro-N⁴-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2,4,5-triamine

A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and2-aminomethyl-4-methoxy-3,5-dimethyl-pyridine was heated to reflux inn-BuOH for 3 h, following the general procedure 1. HPLC RT was 3.597min. ¹HNMR (CDCl₃) δ 8.22 (s, 1H), 7.12 (br. t, 1H), 4.61 (s, 2H),4.56-4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s, 2H), 2.29 (s, 3H), 2.27 (s,3H).

Step 3: Synthesis of7-chloro-3-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of6-chloro-N⁴-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-pyrimidine-2,4,5-triaminewas treated with a cold aqueous solution of NaNO₂, following the generalprocedure 2. HPLC RT was 3.597 min. ¹HNMR (CDCl₃): δ 8.22 (s, 1H), 7.12(broad t, 1H), 4.61 (s, 2H), 4.56-4.55 (d, 2H), 3.80 (s, 3H), 3.00 (s,2H), 2.29 (s, 3H), 2.27 (s, 3H).

Example 27-Chloro-3-(4-methoxy-3,5-dimethyl-1-oxy-pyridin-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by oxidation of7-Chloro-3-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine(see Example 1) with m-CPBA (m-chloroperoxybenzoic acid) in methylenechloride, following the general procedure 4. HPLC RT was 4.780 min.¹HNMR (CDCl₃) δ 8.02 (s, 1H), 5.90 (s, 2H), 5.61 (s, 2H), 3.81 (s, 3H),2.54 (s, 3H), 2.25(s, 3H).

Example 37-Chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: Synthesis of6-chloro-N⁴-(4-methoxy-benzyl)-pyrimidine-2,4,5-triamine:

A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and1-aminomethyl-4-methoxybenzene was refluxed in n-BuOH for 15 h,following the general procedure 1. HPLC RT was 4.675 min. ¹HNMR (CDCl₃)δ 7.29-7.27 (d, 2H), 6.91-6.89 (d, 2H), 5.62 (br. t, 1H) 4.67 (s, 2H),4.56-4.54 (d, 2H), 3.84 (s, 3H), 2.74 (s, 2H).

Step 2: Synthesis of7-chloro-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of 6-chloro-N⁴-(4-methoxy-phenyl)-pyrimidine-2,4,5-triaminewas treated with a cold aqueous solution of NaNO₂, following the generalprocedure 2. HPLC RT was 5.784 min. ¹HNMR (CDCl₃): δ 7.37-7.35 (d, 2H),6.86-6.84 (d, 2H), 5.57 (s, 2H), 5.39 (s, 2H), 3.78 (s, 3H).

Example 4 Synthesis of7-chloro-3-pyridin-2-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: 6-chloro-N-4-pyridin-2-ylmethyl-pyrimidine-2,4,5-triamine

A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and2-aminomethyl-pyridine was refluxed in n-BuOH for 15 h, following thegeneral procedure 1. HPLC RT was 2.573 min.

¹HNMR (CDCl₃) δ 8.60-8.59 (m, 1H), 7.69-7.66 (m, 1H), 7.31-7.29 (m, 1H),7.25-7.20 (m, 1H), 6.55 (br. t, 1H) 4.63 (s, 2H), 4.73-4.71 (d, 2H),1.84 (s, 2H).

Step 2: Synthesis of7-chloro-3-pyridin-2-ylmethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of 6-chloro-N⁴-pyridin-2-ylmethyl-pyrimidine-2,4,5-triaminewas treated with a cold aqueous solution of NaNO₂, following the generalprocedure 2. ¹HNMR (CDCl₃): δ 8.60-8.59 (m, 1H), 7.71-7.67(m, 1H),7.29-7.25 (m, 1H), 7.22-7.20 (m, 1H), 5.81 (s, 2H), 5.48 (s, 2H).

Example 5 Synthesis of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: 6-chloro-N-4-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine

A mixture of 4,6-dichloro-pyrimidine-2,5-diamine and1-aminomethyl-3,4-5-trimethoxybenzene in n-BuOH for 15 h, following thegeneral procedure 1. HPLC RT was 4.458 min. ¹HNMR (CDCl₃) δ 6.58 (s,2H), 5.62 (br. t, 1H) 4.72 (s, 2H), 4.56-4.54 (d, 2H), 3.88 (s, 611),3.86 (s, 3H), 2.77 (s, 2H).

Step 2: Synthesis of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)

A solution of6-chloro-N⁴-(3,4,5-trimethoxy-benzyl)-pyrimidine-2,4,5-triamine wastreated with a cold aqueous solution of NaNO₂, following the generalprocedure 2. HPLC RT was 5.755 min. ¹HNMR (CDCl₃): δ 6.66 (s, 2H), 5.55(s, 2H), 5.42 (s, 2H), 3.83 (s, 3H), 3.80 (s, 6H).

Example 6 Synthesis of7-chloro-3-(2-chloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Chlorination of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)(CF 2137) with NCS (1.5 equivalents) was done following the generalprocedure 3 to give the title compound: HPLC RT was 6.244 min. ¹HNMR(CDCl₃): δ 6.53 (s, 1H), 5.70 (s, 2H), 5.48 (s, 2H), 3.89 (s, 3H), 3.87(s, 3H), 3.75 (s, 3H).

Example 77-Chloro-3-(2,6-dichloro-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Chlorination of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NCS (1.5 equivalents) was done following the general procedure 3 togive the title compound: HPLC RT was 6.616 min. ¹HNMR (CDCl₃): δ 5.81(s, 2H), 5.47 (s, 2H), 3.97 (s, 3H), 3.90(s, 6H).

Example 8 Synthesis of7-chloro-3-(2-bromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Bromination of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NBS (1.5 equivalents) was done following the general procedure 3 togive the title compound: HPLC RT was 6.541 min. ¹HNMR (CDCl₃): δ 6.52(s, 1H), 5.74(s, 2H), 5.46 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.76 (s,3H).

Example 97-Chloro-3-(2,6-dibromo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

Bromination of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NBS (1.5 equivalents) was done following the general procedure 3 togive the title compound: HPLC RT was 6.923 min. ¹HNMR (CDCl₃): δ 5.91(s, 2H>, 5.51 (s, 2H), 3.99 (s, 3H), 3.93(s, 6H).

Example 10 Synthesis of7-chloro-3-(2-iodo-3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained from iodination of7-chloro-3-(3,4,5-trimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NIS (1.5 equivalents) following the general procedure 3. HPLC RTwas 6.497 min. ¹HNMR (CDCl₃): δ 6.47 (s, 1H), 5.73(s, 2H), 5.44 (s, 2H),3.92 (s, 3H), 3.88 (s, 3H), 3.73 (s, 3H).

Example 11 Synthesis of7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: 6-chloro-N-4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine

The title compound was obtained from a mixture of4,6-dichloro-pyrimidine-2,5-diamine and1-aminomethyl-3,5-dimethoxybenzene in n-BuOH for 15 h, following thegeneral procedure 1. HPLC RT was 4.835 min. ¹HNMR (CDCl₃) δ 6.46-6.47(d, 2H), 6.38-6.37(d, 1H), 5.67 (br. t, 1H) 4.63 (s, 2H), 4.53-4.52 (d,2H), 3.81 (s, 6H), 2.72 (s, 2H).

Step 2: Synthesis of7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamin

A solution of6-chloro-N⁴-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treatedwith a cold aqueous solution of NaNO₂, following the general procedure2. HPLC RT was 6.185 min. ¹HNMR (CDCl₃): δ 6.54-6.53 (d, 2H), 6.41-6.40(d, 1H), 5.58 (s, 2H), 5.54 (s, 2H), 3.78 (s, 6H).

Example 12 Synthesis of7-chloro-3-(2-chloro-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by chlorination of7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NCS (1.5 equivalents) in acetic acid at 50° C. for 1 h, followingthe general procedure 3. HPLC RT was 6.467 min. ¹HNMR (CDCl₃): δ6.50-6.49 (d, 1H), 6.18-6.17 (d, 1H), 5.77(s, 2H), 5.44 (s, 2H), 3.91(s, 3H), 3.72 (s, 3H).

Example 13 Synthesis of7-chloro-3-(2-bromo-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by bromination of7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NBS (1.5 equivalents) in acetic acid at 50° C. during 1 h,following the general procedure 3. HPLC RT was 6.573 min. ¹HNMR(d₆-DMSO): δ 7.74 (s, 2H), 6.70-6.69 (d, 1H), 6.23-6.22 (d, 1H), 5.63(s,2H), 3.87 (s, 3H), 3.71 (s, 3H).

Example 14 Synthesis of7-chloro-3-(2-iodo-3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by iodination of7-chloro-3-(3,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NIS (1.5 equivalents) in acetic acid at 50° C. during 1 h,following the general procedure 3. HPLC RT was 6.739 min. ¹HNMR(d₆-DMSO): δ 7.75 (s, 2H), 6.61-6.60 (d, 1H), 6.15-6.14 (d, 1H), 5.58(s,2H), 3.86 (s, 3H), 3.70 (s, 3H).

Example 15 Synthesis of7-Chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamineStep 1: 6-chloro-N⁴-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine

The title compound was obtained from a mixture of4,6-dichloro-pyrimidine-2,5-diamine and1-aminomethyl-2,5-dimethoxybenzene in n-BuOH for 15 h, following thegeneral procedure 1. HPLC RT was 4.601 min. ¹HNMR (CDCl₃) δ 6.91-6.90(d, 1H), 6.82-6.80(m, 2H), 5.82 (br. t, 1H) 4.62 (s, 2H), 4.59-4.58 (d,2H), 3.85 (s, 3H), 2.78 (s, 3H), 2.75 (s, 2H).

Step 2: Synthesis of7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

A solution of6-chloro-N⁴-(2,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treatedwith a cold aqueous solution of NaNO₂, following the general procedure2. HPLC RT was 6.130 min. ¹HNMR (CDCl₃): δ 6.84-6.83 (m, 2H), 6.64-6.63(d, 1H), 5.67 (s, 2H), 5.54 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H).

Example 16 Synthesis of7-chloro-3-(4-bromo-2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by bromination of7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NBS (1.5 equivalents) in acetic acid at 50° C. during 1 h,following the general procedure 3. HPLC RT was 6.438 min. ¹HNMR (CDCl₃):δ 7.11 (s, 1H), 6.80 (s, 1H), 5.63 (s, 2H), 5.57 (s, 2H), 3.82 (s, 3H),3.79 (s, 3H).

Example 17 Synthesis of7-chloro-3-(3-chloro-2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine

The title compound was obtained by chlorination of7-chloro-3-(2,5-dimethoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine)with NCS (1.5 equivalents) in acetic acid at 50° C. during 1 h,following the general procedure 3. HPLC RT was 6.392 min. ¹HNMR (CDCl₃):δ 6.91-6.90 (d, 1H), 6.67-6.66 (d, 1H), 5.70 (s, 2H), 5.43(s, 2H), 3.92(s, 3H), 3.73 (s, 3H).

BIOLOGY EXAMPLES Example A rHSP90 Competitive Binding Assay

Five microgram of purified rHSP90 protein (Stressgen, BC, Canada,#SPP-770) in phosphated buffered saline (PBS) was coated on 96 wellplates by incubating overnight at 4° C. Unbound protein was removed andthe coated wells were washed twice with 200 μL PBS. DMSO controls(considered as untreated samples) or test compounds were then added at100-30-10-3-1-0.3 μM dilutions (in PBS), the plates mixed for 30 secondson the plate shaker, and then incubated for 60 min. at 37° C. The wellswere washed twice with 200 μL PBS, and 10 μM biotinylated-geldanamycin(biotin-GM) was added and incubated for 60 min. at 37° C. The wells werewashed again twice with 200 μL PBS, before the addition of 201 g/mLstreptavidin-phycoerythrin (streptavidin-PE) (Molecular Probes, Eugene,Oreg.) and incubation for 60 min. at 37° C. The wells were washed againtwice with 200 μL PBS. Relative fluorescence units (RFU) was measuredusing a SpectraMax Gemini XS Spectrofluorometer (Molecular Devices,Sunnyvale, Calif.) with an excitation at 485 nm and emission at 580 nm;data was acquired using SOFTmax®PRO software (Molecular DevicesCorporation, Sunnyvale, Calif.). The background was defined as the RFUgenerated from wells that were not coated with HSP90 but were treatedwith the biotin-GM and streptavidin-PE. The background measurements weresubstrated from each sample treated with biotin-GM and streptavidin-PEmeasurements before other computation. Percent inhibition of binding foreach sample was calculated from the background subtracted values asfollows:% binding inhibition=[RFU untreated−RFU treated]/RFU untreated]×100.

Example B Cell Lysate Binding Assay

MCF7 breast carcinoma cell lysates were prepared by douncing in lysingbuffer (20 mM HEPES, pH 7.3, 1 mM EDTA, 5 mM MgCl₂, 100 mM KCl), andthen incubated with or without test compound for 30 mins at 4° C.,followed by incubation with biotin-GM linked to BioMag™ streptavidinmagnetic beads (Qiagen) for 1 hr at 4° C. The tubes were placed on amagnetic rack, and the unbound supernatant removed. The magnetic beadswere washed three times in lysis buffer and boiled for 5 mins at 95° C.in SDS-PAGE sample buffer. Samples were analyzed on SDS protein gels,and Western blots done for rHSP90. Bands in the Western Blots werequantitated using the Bio-rad Fluor-S MultiImager, and the % inhibitionof binding of rHSP90 to the biotin-GM was calculated.

The lysate binding ability of selected compounds of the invention basedon the above assay is summarized in Table 2. The IC₅₀ reported is theconcentration of test compound needed to achieve 50% inhibition of thebiotin-GM binding to rHSP90 in the MCF7 cell lysates.

Example C. HER2 Degradation Assay

MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's modifiedEagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and 10 mMHEPES, and plated in 24 well plates (50% confluent). Twenty-four hrslater (cells are 65-70% confluent), test compounds were added andincubated overnight for 16 h. For the less potent compounds, the amountsadded were 100 μM, 30 μM, 10 μM and 1 μM, and for more potent compounds,the amounts added were 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM and 0.003μM. The wells were washed with 1 mL phosphate buffered saline (PBS), and200 μL trypsin was added to each well. After trypsinization wascomplete, 50 μL of FBS was added to each well. Then 200 μL cells wastransferred to 96 well plates. The cells were pipetted up and down toobtain a single cell suspension. The plates were centrifuged at 2,500rpm for 1 min using a Sorvall Legend RT™ tabletop centrifuge (KendroLaboratory Products, Asheville, N.C.). The cells were then washed oncein PBS containing 0.2% BSA and 0.2% sodium azide (BA buffer).Phycoerythrin (PE) conjugated anti HER2/Neu antibody (Becton Dickinson,#340552), or PE conjugated anti-keyhole limpet hemacyanin [KLH] (BectonDickinson, #340761) control antibody was added at a dilution of 1:20 and1:40 respectively (final concentration was 1 μg/mL) and the cells werepipeted up and down to form a single cell suspension, and incubated for15 mins. The cells were washed twice with 200 μL BA buffer, andresuspended in 200 μL BA buffer, and transferred to FACSCAN tubes withan additional 250 μL BA buffer. Samples were analyzed using aFACSCalibur™ flow cytometer (Becton Dickinson, San Jose, Calif.)equipped with Argon-ion laser that emits 15 mW of 488 nm light forexcitation of the PE fluorochrome. 10,000 events were collected persample. A fluorescence histogram was generated and the mean fluorescenceintensity (MFI) of each sample was determined using Cellquest software.The background was defined as the MFI generated from cells incubatedwith control IgG-PE, and was subtracted from each sample stained withthe HER2/Neu antibody. Cells incubated with DMSO was always done asuntreated controls since the compounds were resuspended in DMSO. Percentdegradation of HER2 was calculated as follows:% HER2 degraded=[(MFl untreated cells−MFl treated cells)/MFl untreatedcell]×100

The HER2 degradation ability of selected compounds of the inventionbased on this assay is summarized in Table 2. IC₅₀ is defined as theconcentration at which there was 50% degradation of the HER2/Neuprotein.

Example D MTS Assay

MTS assays measures the cytotoxicity of geldanamycin derivatives. MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazoliumis a tetrazolium dye that is converted to a formazan product bydehydrogenase enzymes of metabolically active cells (Corey, A. et al.“Use of an aqueous soluble tetrazolium/formazan assay for cell growthassays in culture,” Cancer Commun. 1991, 3, 207-212). Cells were seededin 96 well plates at 2000 cells/well and allowed to adhere overnight inDulbecco's modified Eagle's medium supplemented with 10% fetal bovineserum. The final culture volume was 100 μl. Viable cell number wasdetermined by using the Celltiter 96 AQ_(ueous) Non-radioactive CellProliferation Assay (Promega, Madison Wis.). The MTS/PMS (phenazinemethosulfate) solution was mixed at a ratio of 20:1, and 20 μL was addedper well to 100 μl of culture medium. After 2-4 hours, the formation ofthe formazan product was measured at 490 nm absorbance using a multiwellplate spectrophotometer. Background was determined by measuring the Abs490 nm of cell culture medium and MTS-PMS in the absence of cells andwas subtracted from all values. Percent viable cells was calculated asfollows:% viable cells=(Abs at 490 nm treated cells/Abs at 490 nm untreatedcells)×100

The effect of selected compounds of the invention on MCF7 breastcarcinoma cells according to the MTS assay is summarized in Table 2.IC₅₀ was defined as the concentration of the compound which gave rise to50% viable cell number. TABLE 2 Biological Activities of SelectedCompounds of Formula I Formula 1

HER2 MTS IC₅₀ IC₅₀ S.No. Ex.# Structure (μM) (μM) 1 5

15.0 ND 2 1

0.4 8.0 3 7

4.0 ND 4 6

12.0 ND 5 9

6.3 ND 6 8

6.5 ND 7 10

10.0 ND 8 12

8.5 ND 9 13

16.0 ND 10 16

22.0 ND 11 17

19.0 ND 12 2

0.5 NDND = not determined

The examples are not limiting and are merely illustrative of variousaspects and embodiment of the present invention. All documents citedherein are indicative of the levels of skill in the art to which theinvention pertains and are incorporated by reference herein in theirentireties. None, however, is admitted to be prior art.

One skilled in the art will readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described illustrate preferred embodiments, areexemplary, and are not intended as limitations on the scope of theinvention. Certain modifications and other uses will occur to thoseskilled in the art, and are encompassed within the sprint of theinvention, as defined by the scope of the claims.

The invention illustratively described herein suitably may be practicedin the absence of any element or elements, limitation or limitationswhich is not specifically disclosed herein. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed, or portions thereof. It is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments, optional features,modifications and variations of the concepts herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention asdefined by the description and the appended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, e.g.,genuses, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group or subgenus, and exclusions of individualmembers as appropriate, e.g., by proviso.

Other embodiments are within the following claims.

1. A compound represented by Formula I, or a polymorph, solvate, ester,tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt orprodrug thereof,

wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl; R² is —NHR⁸; R⁴ is—CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—; R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, wherein: the aryl group is substituted with3 to 5 substituents, the heteroaryl group is substituted with 2 to 5substituents, the alicyclic group is substituted with 3 to 5substituents, the heterocyclic group is substituted with 3 to 5substituents, and the substituents are selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,—OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R⁹;R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lowerheteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, orlower alkynyl, R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lowerheteroaryl or lower aryl; and R¹² is hydrogen or lower alkyl; providedthat when R⁵ is alicyclic, the ring system does not contain anytetra-substituted sp³ ring carbons.
 2. The compound of claim 1, or apolymorph, solvate, ester, tautomer, enantiomer, diastereomer,pharmaceutically acceptable salt or prodrug thereof, wherein each ofsaid aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic orbicyclic.
 3. The compound of claim 1, or a polymorph, solvate, ester,tautomer, enantiomer, diastereomer, pharmaceutically acceptable salt orprodrug thereof, wherein: R¹ is halogen; and R² is —NHR⁸, where R⁸ ishydrogen or —C(O)R⁹.
 4. The compound of claim 1, or a polymorph,solvate, ester, tautomer, enantiomer, pharmaceutically acceptable saltor prodrug thereof, wherein: R¹ is chloro or bromo, R² is —NHR⁸, whereR⁸ is hydrogen or —C(O)R⁹; and R⁴ is —CHR¹²,
 5. The compound of claim 1,or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein: R² is —NHR⁸, where R⁸ ishydrogen or —C(O)R⁹; and R⁴ is —CH₂—.
 6. The compound of claim 1, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein: R¹ is chloro or bromo; R²is —NH₂, R⁴ is —CH₂—; and R⁵ is aryl or heteroaryl, wherein each of thearyl and heteroaryl is monocyclic or bicyclic and is substituted with 3to 5 substituents.
 7. The compound of claim 6, or a polymorph, solvate,ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrugthereof, wherein R¹ is chloro or bromo, R² is —NH₂, and R⁵ is a phenylhaving at least three substituents.
 8. The compound of claim 6, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein R¹ is chloro or bromo, R² is—NH₂ and R⁵ is a pyridyl having at least two substituents.
 9. Thecompound of claim 6, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof, whereinR¹ is chloro or bromo, R² is —NH₂, and R⁵ is 1-oxy-pyridyl(N-oxy-pyridyl) having at least two substituents.
 10. The compound ofclaim 6, wherein the compound is a member selected from the group below,or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof:


11. The compound of claim 6, wherein the compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


12. The compound of claim 6, wherein the compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof:


13. The compound of claim 6, wherein the compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomers, pharmaceutically acceptable salt or prodrug thereof:


14. The compound of claim 6, wherein the compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomers, pharmaceutically acceptable salt or prodrug thereof:


15. The compound of claim 6, wherein the compound is a member selectedfrom the group below, or a polymorph, solvate, ester, tautomer,enantiomers, pharmaceutically acceptable salt or prodrug thereof:


16. The compound of claim 6, wherein the compound is represented by theformula below, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof:


17. The compound of claim 6, wherein the compound is represented by theformula below, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof:


18. The compound of claim 6, wherein the compound is represented by theformula below, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof:


19. The compound of claim 6, wherein the compound is represented by theformula below, or a polymorph, solvate, ester, tautomer,pharmaceutically acceptable salt or prodrug thereof:


20. A pharmaceutical composition comprising one or more pharmaceuticalacceptable excipient and at least one compound represented by Formula Ibelow, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof,

wherein: R¹ is halogen, —OR¹¹, —SR¹¹ or lower alkyl; R² is —NHR⁸; R⁴ is—CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—; R⁵ is aryl, heteroaryl,alicyclic, or heterocyclic, wherein: the aryl group is substituted with3 to 5 substituents, the heteroaryl group is substituted with 2 to 5substituents, the alicyclic group is substituted with 3 to 5substituents, the heterocyclic group is substituted with 3 to 5substituents, and the substituents are selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,—OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R⁹;R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lowerheteroaryl, —NR¹⁰R¹⁰, or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, orlower alkynyl, R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lowerheteroaryl or lower aryl; and R¹² is hydrogen or lower alkyl; providedthat when R⁵ is alicyclic, the ring system does not contain anytetra-substituted sp³ ring carbons.
 21. The pharmaceutical compositionof claim 20, wherein: R¹ is halogen; R² is —NH₂, R⁴ is —CH₂—; and R⁵ isaryl or heteroaryl, wherein each of the aryl and heteroaryl ismonocyclic or bicyclic and is substituted with 3 to 5 substituents. 22.A method of treating an individual having an HSP90 mediated disordercomprising administering to said individual a pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound of FormulaI:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein: R¹ is halogen, —OR¹¹, —SR¹¹or lower alkyl; R² is —NHR⁸; R⁴ is —CHR¹²—, —C(O)—, —C(S)—, —S(O)— or—SO₂—; R⁵ is aryl, heteroaryl, alicyclic, or heterocyclic, wherein: thearyl group is substituted with 3 to 5 substituents, the heteroaryl groupis substituted with 2 to 5 substituents, the alicyclic group issubstituted with 3 to 5 substituents, the heterocyclic group issubstituted with 3 to 5 substituents, and the substituents are selectedfrom the group consisting of halogen, lower alkyl, lower alkenyl, loweralkynyl, —SR⁸, —OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl,heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl,amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa,perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl,thiophene, furanyl, indole, indazole, phosphonates, phosphates,phosphoramides, sulfonates, sulfones, sulfates, sulphonamides,carbamates, ureas, thioureas and thioamides, wherein R⁸ and R¹⁰ takentogether optionally form a ring of 3-7 ring atoms and optionally 1-3 ofthe ring atoms are heteroatoms selected from the group of O, S and N; R⁸is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl,lower heteroaryl, or —C(O)R⁹; R⁹ is H, lower alkyl, lower alkenyl, loweralkynyl, lower aryl, lower heteroaryl, —NR¹⁰R¹⁰ or —OR¹¹, wherein R¹⁰and R¹⁰ taken together optionally form a ring of 3-7 ring atoms andoptionally 1-3 of the ring atoms are heteroatoms selected from the groupof O, S and N; R¹⁰ is hydrogen, lower alkyl, lower heteroaryl, loweraryl, lower alkenyl, or lower alkynyl, R¹¹ is lower alkyl, loweralkenyl, lower alkynyl, lower heteroaryl or lower aryl; and R¹² ishydrogen or lower alkyl; provided that when R⁵ is alicyclic, the ringsystem does not contain any tetra-substituted sp³ ring carbons.
 23. Themethod of claim 22, wherein: R¹ is halogen; R² is —NH₂, R⁴ is —CH₂—; andR⁵ is aryl or heteroaryl, wherein each of the aryl and heteroaryl ismonocyclic or bicyclic and is substituted with 3 to 5 substituents. 24.The method of claim 22, wherein R¹ is chloro or bromo, R² is —NH₂, andR⁵ is a phenyl having at least three substituents.
 25. The method ofclaim 22, wherein R¹ is chloro or bromo, R² is —NH₂ and R⁵ is a pyridylhaving at least two substituents.
 26. The method of claim 22, wherein R¹is chloro or bromo, R² is —NH₂, and R⁵ is an 1-oxy-pyridyl(N-oxy-pyridyl) having at least two substituents.
 27. The method ofclaim 22, wherein the HSP90 mediated disorder is selected from the groupof inflammatory diseases, infections, autoimmune disorders, stroke,ischemia, cardiac disorders, neurological disorders, fibrogeneticdisorders, proliferative disorders, tumors, leukemias, neoplasms,cancers, carcinomas, metabolic diseases, and malignant disease.
 28. Themethod of claim 27 wherein the fibrogenetic disorder is further selectedfrom the group of scleroderma, polymyositis, systemic lupus, rheumatoidarthritis, liver cirrhosis, keloid formation, interstitial nephritis andpulmonary fibrosis.
 29. The method of claim 22, further comprisingadministering at least one therapeutic agent selected from the group ofcytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.30. The method of claim 29, wherein the at least one anti-neoplasticagent is selected from the group of alkylating agents, anti-metabolites,epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents, and haematopoietic growthfactors.
 31. A compound, or a polymorph, solvate, ester, tautomer,enantiomer, pharmaceutically acceptable salt or prodrug thereof,prepared by the process comprising: reacting a compound of formula Y anda compound of formula Z, wherein: Y is a represented by any one of thefollowing formulae:

Z is L¹-R⁴—R⁵; wherein: L¹ is halogen, NR⁸R¹⁰ triflate, tosylate, ormesylate; R⁴ is —CHR¹²—, —C(O)—, —C(S)—, —S(O)— or —SO₂—; R⁵ is aryl,heteroaryl, alicyclic, or heterocyclic, wherein: the aryl group issubstituted with 3 to 5 substituents, the heteroaryl group issubstituted with 2 to 5 substituents, the alicyclic group is substitutedwith 3 to 5 substituents, the heterocyclic group is substituted with 3to 5 substituents, and the substituents are selected from the groupconsisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR⁸,—OR⁸, —CN, —C(O)OH, —C(O)R⁹, —NO₂, —NR⁸R¹⁰ lower aryl, heteroaryl,alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino,alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl,perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl,indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates,sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas andthioamides, wherein R⁸ and R¹⁰ taken together optionally form a ring of3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatomsselected from the group of O, S and N; R⁸ is hydrogen, lower alkyl,lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R⁹;R⁹ is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lowerheteroaryl, —NR¹⁰R¹⁰, or —OR¹¹, wherein R¹⁰ and R¹⁰ taken togetheroptionally form a ring of 3-7 ring atoms and optionally 1-3 of the ringatoms are heteroatoms selected from the group of O, S and N; R¹⁰ ishydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, orlower alkynyl, R¹¹ is lower alkyl, lower alkenyl, lower alkynyl, lowerheteroaryl or lower aryl; R¹² is hydrogen or lower alkyl; R²¹ ishalogen, —OR⁸, —SR⁸ or lower alkyl; R²² is —NR⁸R¹⁰; R²⁴ is —NH₂, —NO₂ or—NO; R²⁵ is halogen or —OH; R²⁶ is —C(O)NH₂ or C(O)OEt; and R²⁷ is —NH₂,—OH or halogen; provided that when R⁵ is alicyclic, the ring system doesnot contain any tetra-substituted sp³ ring carbons.
 32. The compound ofclaim 30, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein L¹ is —Cl,—Br or —NH₂; R⁵ is aryl or heteroaryl.
 33. The compound of claim 32, ora polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, R⁴ is —CH₂—.
 34. The compound ofclaim 32, or a polymorph, solvate, ester, tautomer, enantiomer,pharmaceutically acceptable salt or prodrug thereof, wherein saidreaction is performed in a solvent comprising a member selected from thegroup of DMF, THF and DMSO.
 35. The compound of claim 32, or apolymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug, thereof, wherein said reaction is performedin a solvent that comprises DMF.